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Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment

Cite this: ACS Med. Chem. Lett. 2020, 11, 7, 1361–1366
Publication Date (Web):June 23, 2020
https://doi.org/10.1021/acsmedchemlett.0c00316

Copyright © 2020 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

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While remdesivir has garnered much hope for its moderate anti-Covid-19 effects, its parent nucleoside, GS-441524, has been overlooked. Pharmacokinetic analysis of remdesivir evidences premature serum hydrolysis to GS-441524; GS-441524 is the predominant metabolite reaching the lungs. With its synthetic simplicity and in vivo efficacy in the veterinary setting, we contend that GS-441524 is superior to remdesivir for Covid-19 treatment.

KEYWORDS:
While remdesivir has demonstrated efficacy against Covid-19, its broad translational applicability has been hampered by limited supply and distribution (1) due to the difficulty of its synthesis (2) and its obligatory intravenous (IV) administration requiring an inpatient setting. We recently described in a general audience publication (3) the advantages that the parent nucleoside of remdesivir, GS-441524, has over remdesivir itself for the treatment of Covid-19. Fundamentally, our investigation into the metabolism of remdesivir evidences premature serum hydrolysis of its phosphate prodrug, followed by dephosphorylation. (4−6) As a result, the major metabolite circulating in the bloodstream is the parent nucleoside, GS-441524, even though remdesivir (monophosphate nucleotide prodrug) was the species initially administered. Accounting for this broader pharmacokinetic (PK) rationale, we herein provide a detailed analysis of the literature that supports the use of GS-441524 over remdesivir for the treatment of Covid-19.

The Phosphate Prodrug on Remdesivir Is Not Intended for Lung-Specific Delivery

Remdesivir is a structural analogue of adenosine monophosphate (AMP) that interferes with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). (7) The anionic phosphate moiety on remdesivir is masked by McGuigan prodrug moieties (8) (phenol and l-alaninate ethylbutyl ester) to enhance cell permeability. In principle, these prodrug moieties would be removed intracellularly—first by esterases (cathepsin A/carboxylesterase 1) and then by phosphoramidases (HINT1-3) (9) to release the monophosphorylated nucleotide. This would then be phosphorylated twice to give the active NTP (7,9) (Figure 1a), which is substrate-competitive with ATP for incorporation by viral RdRp and inhibition of viral RNA synthesis. (7) The McGuigan phosphate prodrug was partly developed to overcome the perceived rate-limiting first phosphorylation step toward the active triphosphorylated species. Bioactivation of the prodrug first involves carboxylesterases (CES1) and cathepsin A (CTSA), followed by phosphoramidases (histidine triad nucleotide binding proteins; HINTs; Figure 1a). (9−11) Protein expression data from the Human Protein Atlas show that these enzymes (CES1, CTSA, HINT1, 2, 3) all have high expression in the liver, with minimal expression in type II pneumocytes in the lung (12) (Figure 2). For the HINT family of phosphoramidases, there is some slight variation in each isoform’s tissue-specific expression (Figure 2b, c); however, all 3 isoforms show high expression in the GI tract, liver, and kidneys. From the pattern of bioactivation for McGuigan prodrugs, it follows that the most significant accumulation active NTP will be in cell types with high expression of CES1/CTSA/HINT1-3, such as the liver. Preferential bioactivation of McGuigan prodrugs such as remdesivir could explain the grade 3/4 adverse events related to liver and kidney damage in Covid-19 patients treated with remdesivir. (13) Seeing that the enzymes involved in McGuigan prodrug hydrolysis are hardly expressed in the lungs undermines its utility in the context of a primarily respiratory disease such as Covid-19.

Figure 1

Figure 1. McGuigan prodrugs on remdesivir are prematurely hydrolyzed in serum. (A) The ideal bioactivation of remdesivir predominately occurs in vitro. (B) The presence of serum enzymes in vivo predominately results in premature hydrolysis of the phosphate prodrugs, followed by dephosphorylation to the nucleoside, GS-441524.

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Figure 2

Figure 2. McGuigan prodrugs on remdesivir are preferentially bioactivated in the liver. (A) Labile prodrug moieties on remdesivir with corresponding bioactivation enzymes. (B) Relative tissue mRNA expression of initial prodrug bioactivating enzymes for RDV (CES1/CTSA/HINT1) adapted from the HPA data set on the Human Protein Atlas reported as median-centered protein-coding transcripts per million (pTPM). Overall, McGuigan prodrug bioactivating enzymes are more highly expressed in the liver than in the lungs. (C) Immunohistochemistry images from the Human Protein Atlas indicating expression for ProTide bioactivating enzymes. Brown regions indicate enzyme expression while blue regions indicate absent expression. For the lung, pneumocytes—cells frequently infected by Covid-19—are characterized by a threadlike appearance. Expression in the liver is generally higher compared to lung for all enzymes. For CTSA, darkly stained regions are associated with macrophages. IHC images for the skin are included to show lack of enzyme expression. Antibodies used: CTSA (CAB024930), CES1 (HPA046717), HINT1 (HPA044577).

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GS-441524 Is the Predominant Metabolite in the Bloodstream When Remdesivir Is Administered IV

Hydrolytic enzymes are ubiquitous in serum. (14) This is one physiological factor that, especially for prodrugs, (15) prevents direct extrapolation of bioactivation mechanisms observed in vitro to the in vivo setting. For example, esterases and phosphatases are abundantly present in serum across species. (16,17) Premature serum hydrolysis of the McGuigan prodrug on remdesivir is thus unsurprising (Figure 1b). Multiple studies have demonstrated that the nucleoside, GS-441524, is the predominant species in serum after remdesivir is administered (Figure 3b, c). (4−6) All studies that have investigated the PK of remdesivir in nonhuman primates (NHP) have concluded that intact remdesivir exhibits a short plasma half-life of about 0.4 h in serum, with “persistence” of the downstream nucleoside, GS-441524 (Figure 3c). (4,6) IV injection of remdesivir in NHP results in GS-441524 being present in serum at concentrations 1000-fold higher than remdesivir throughout a 7-day treatment course (6) (Figure 3b). This recurring phenomenon can first be explained by the abundance of plasma esterases, as the phosphoramidases (HINT1) involved in removal of the l-alanine have a strictly intracellular presence (see Human Protein Atlas HINT1). Inadvertent biotransformation of remdesivir to GS-441524 can be explained by the following sequence: (1) esterase removal of the l-alaninate ester, (2) intramolecular cyclization, displacement of the phenolate, followed by reopening of the ring, (3) cleavage of the phosphate ester by serum phosphatases or nucleosidases (Figure 1b). The proposed serum bioactivation mechanism accounts for the general substrate constraints for each class of enzyme. For instance, CES1 is named as one of the enzymes involved in McGuigan prodrug hydrolysis. However, this does not preclude other esterases from acting on its l-alaninate ester. A study conducted by Sheahan and colleagues specifically investigated the PK of remdesivir in carboxylesterase 1c deficient mice (Ces1c–/–). (5) Even in this Ces1c–/– model, the half-life of remdesivir was still short (t1/2 ∼ 25 min), supporting the notion that other esterases are capable of performing the initial hydrolysis reaction. Thus, the abundance of hydrolytic enzymes in serum explains the persistent, multispecies observation that GS-441524 is the predominant metabolite when remdesivir is administered. (4−6) For the fleeting duration of time that remdesivir is in the blood (prior to hydrolysis to GS-441524), the expression of bioactivating enzymes for McGuigan prodrugs suggests that the highest concentrations of NTP formation by remdesivir—rather than GS-441524—would occur in cell types with high expression of CES1/CTSA/HINT1. This largely favors the liver over the lungs (Figure 2). Differential expression of prodrug bioactivating enzymes likely explains the wide range of EC50 values with remdesivir in vitro. (18−20)

Figure 3

Figure 3. Unlike remdesivir, GS-441524 persists in serum at concentrations above the EC50 value required against SARS-CoV-infected primary HAE cells for long durations. (A) In vitro potency data replotted from Agostini et al. mBio, 2018. (2) Primary HAE cells were infected with either MERS-CoV or SARS-CoV and treated with either GS-441524 (open squares) or remdesivir (closed circles). Mean EC50 of GS-441524 for SARS-CoV-infected HAE cells was found to be 0.18 ± 0.14 μM (note large standard deviations, red arrows). A study by Murphy et al. shows that GS-441524 has an EC50 value of 0.78 μM against FCoV-infected CRFK cells (red dashed line), (22) which is higher than the EC50 value for GS-441524 against SARS-CoV-infected primary HAE cells. (B) Estimated metabolite concentrations for a PK experiment in a SARS-CoV-2 primate model replotted from Williamson et al. Nature, 2020. (6) Primates were initially injected IV with 10 mg/kg of remdesivir 12 h postinoculation with SARS-CoV-2 and then 5 mg/kg of remdesivir every 24 h after. Throughout the experiment, GS-441524 is present in serum at concentrations ∼1000-fold higher than remdesivir; the concentration of GS-441524 is consistently above the EC50 value in SARS-CoV-infected primary HAE cells (red dashed line) at all time points taken in the experiment. In contrast, the concentration of remdesivir in serum never exceeds that required to give the EC50 value against SARS-CoV-infected primary HAE cells (gray dashed line). (C) PK data replotted from Warren et al. Nature, 2016 (3) following IV injection (10 mg/kg) of remdesivir in NHP. Dashed lines indicate the approximate EC50 values of GS-441524 (red) or remdesivir (gray) needed to reach EC50 in SARS-CoV primary HAE cells obtained in (A). Unlike remdesivir, the concentration of drug required to give the EC50 value against SARS-CoV primary HAE cells is maintained for significantly longer with GS-441524 than with remdesivir.

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GS-441524 Is Exceptionally Effective and Well-Tolerated against Clinical Presentations of Feline Coronavirus

There are currently no studies that have compared the antiviral activities of remdesivir and GS-441524 in vivo, with most focusing exclusively on remdesivir. Where GS-441524 has been investigated in vivo is in the veterinary setting. (21−23) Cats infected with feline coronavirus (FCoV) present with a serious disease known as feline infectious peritonitis (FIP). While long considered fatal in its severe manifestations, (24) a study conducted by Pedersen and colleagues showed that GS-441524 is capable of treating cats suffering from FIP with a 96% cure rate. (21) Pedersen noted the “impressive” safety profile of GS-441524, with no systemic signs of toxicity observed when administered subcutaneously at 4 mg/kg. (21) In a more recent study, Pedersen and colleagues escalated the dose of GS-441524 (5–10 mg/kg) to treat neurological manifestations of FIP; this translates to about 350–700 mg in a 70 kg human, greatly exceeding the dose currently given to patients treated with remdesivir (200 mg loading, then 100 mg). (13,25) Even at these higher doses, they found that GS-441524 treatment resulted in the long term resolution of neurological FIP with an excellent safety profile: minimal dose-related toxicities were observed. (23)

GS-441524 Shows Comparable Efficacy in Cell-Based Models of Primary Human Lung and Cat Cells Infected with Coronavirus

In vitro potency comparisons between GS-441524 and remdesivir are ultimately moot in the context of respiratory diseases such as SARS-CoV-2, if GS-441524 is the predominant species that reaches the lungs. To better gauge the efficacy of GS-441524 against SARS-CoV-2, it is helpful to first compare EC50 values between coronavirus infected human and cat cells, as the clinical efficacy of GS-441524 has already been well-established in cats. (21) GS-441524 has an EC50 value of 0.78 μM in CRFK cells infected with FCoV (Figure 3a). (26) At the time of publication, a study by Agostini and colleagues is the only report that has compared the antiviral activities of GS-441524 and remdesivir in primary human airway epithelial (HAE) cells, the most clinically relevant in vitro model of the lung, infected with either SARS-CoV or MERS-CoV. (27) While the mean EC50 value of remdesivir is lower for both SARS-CoV and MERS-CoV-infected cells, close inspection of the data reveals large standard deviations between the EC50 values obtained from GS-441524 and remdesivir making these potency differences not statistically significant (Figure 3a). (27) For instance, against SARS-CoV-infected HAE cells, GS-441524 has a reported EC50 of 0.18 (±0.14) μM, which is comparable, if not lower, than that required to exert antiviral activity against FCoV-infected cells in vitro. Most significantly, the EC50 concentration for GS-441524 against SARS-CoV-infected primary HAE cells is sustained in the plasma of NHP for nearly the entire duration of the single-dose, 24 h PK experiment conducted by Warren and colleagues (Figure 3c). In contrast, the EC50 concentration for remdesivir against SARS-CoV-infected primary HAE cells diminishes after ∼2 h. The dominance of GS-441524 over remdesivir in serum was even more pronounced in Williamson’s 7-day PK study, in which GS-441524 was present in serum at concentrations 1,000-fold greater than remdesivir at every measured time point (Figure 3b). (6) Coupled with the robust antiviral activity that GS-441524 has demonstrated against FIP, these data compel further investigations into the therapeutic and prophylactic utility of GS-441524 against SARS-CoV-2 in patients.

Concluding Remarks

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SARS-CoV-2 is a respiratory virus that primarily affects the lungs. (12) While remdesivir has shown some efficacy in patients with advanced Covid-19, (13) its phosphate prodrug is fundamentally not designed for lung-specific delivery. Enzymes that activate the McGuigan prodrug are preferentially expressed in tissues such as the liver, which results in uneven distribution of active NTP formation via remdesivir that disfavors the lungs. Practically, the structural complexity of the McGuigan prodrug (28) adds unnecessary synthetic difficulty that hampers mass production and impedes distribution. (1) Above all else, premature hydrolysis of the McGuigan prodrug, followed by dephosphorylation in serum such that GS-441524 is the predominant metabolite (4,5,29) compels studies investigating its utility in patients with Covid-19. In contrast to the prodrug activating enzymes that activate remdesivir, bioactivation of GS-441524 relies on expression of the kinase responsible for initial phosphorylation (likely adenosine kinase, ADK). According to the Human Protein Atlas, ADK is moderately expressed across all tissues, suggesting that administration of GS-441524 would result in even distribution across tissues. The remarkable safety profile of GS-441524, indicated by selectivity indices in vitro (EC50/CC50 ratio) (2,19,30) and by clinical observations in cats, (21−23) suggest that higher dosing and lung NTP loading could be achieved with GS-441524 without encountering serious adverse effects. GS-441524 is also a structurally simple molecule that is easier to synthesize compared to remdesivir, (2) which would ease mass production and distribution. Especially amidst the documented premature serum hydrolysis of remdesivir to GS-441524, (4,5,29) we see several advantages to using GS-441524 over remdesivir for patients with Covid-19. While GS-441524, is not included in the emergency use authorization of remdesivir, the exigence of the pandemic may allow ordinary regulatory hurdles to be overcome, especially as these two drugs yield the same active species. An investigational new drug (IND) waiver or an emergency IND could be filed. The FDA has previously made allowances for prodrugs and their corresponding active substances, as in the case of Lenflunomide/Teriflunomide. Further investigations into the anti-Covid-19 utility of GS-441524 are thus imperative.

Author Information

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  • Corresponding Author
  • Author
    • Florian L. Muller - Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, United States;  Orcidhttp://orcid.org/0000-0001-7568-2948
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank Niels Pedersen, Steve Kirsch, and David Piwnica-Worms for helpful discussions, Cong-Dat Pham for assistance with research, and Pat Skerrett for assistance with our general audience article published in STAT. This work was supported by the American Cancer Society (RSG-15-145-01-CDD).

References

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    The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-iso-Pr ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equiv. surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be crit. to the effectiveness of GS-6620 in nonclin. species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concn. Higher rates of metab. were obsd. at lower concns. that were unable to sat. intestinal efflux transporters. In first-in-human clin. trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that obsd. in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3'-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metab. and relatively poor oral absorption in humans.
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  10. 10
    Bieganowski, P.; Garrison, P. N.; Hodawadekar, S. C.; Faye, G.; Barnes, L. D.; Brenner, C. Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3. J. Biol. Chem. 2002, 277 (13), 10852– 10860,  DOI: 10.1074/jbc.M111480200
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    10
    Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3
    Bieganowski, Pawel; Garrison, Preston N.; Hodawadekar, Santosh C.; Faye, Gerard; Barnes, Larry D.; Brenner, Charles
    Journal of Biological Chemistry (2002), 277 (13), 10852-10860CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The histidine triad superfamily of nucleotide hydrolases and nucleotide transferases consists of a branch of proteins related to Hint and Aprataxin, a branch of Fhit-related hydrolases, and a branch of galactose-1-phosphate uridylytransferase (GalT)-related transferases. Although substrates of Fhit and GalT are known and consequences of mutations in Aprataxin, Fhit, and GalT are known, good substrates had not been reported for any member of the Hint branch, and mutational consequences were unknown for Hint orthologs, which are the most ancient and widespread proteins in the Hint branch and in the histidine triad superfamily. Here we show that rabbit and yeast Hint hydrolyze the natural product adenosine-5'-monophosphoramidate (AMPNH2) in an active-site-dependent manner at second order rates exceeding 1,000,000 M-1 S-1. Yeast strains constructed with specific loss of the Hnt1 active site fail to grow on galactose at elevated temps. Loss of Hnt1 enzyme activity also leads to hypersensitivity to mutations in Ccl1, Tfb3, and Kin28, which constitute the TFIIK kinase subcomplex of general transcription factor TFIIH and to mutations in Cak1, which phosphorylates Kin28. The target of Hnt1 regulation in this pathway was shown to be downstream of Cak1 and not to affect stability of Kin28 monomers. Functional complementation of all Hnt1 phenotypes was provided by rabbit Hint, which is only 22% identical to yeast Hnt1 but has very similar adenosine monophosphoramidase activity.
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  11. 11
    Chou, T.-F.; Baraniak, J.; Kaczmarek, R.; Zhou, X.; Cheng, J.; Ghosh, B.; Wagner, C. R. Phosphoramidate Pronucleotides: A Comparison of the Phosphoramidase Substrate Specificity of Human and Escherichia Coli Histidine Triad Nucleotide Binding Proteins. Mol. Pharmaceutics 2007, 4 (2), 208– 217,  DOI: 10.1021/mp060070y
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    11
    Phosphoramidate Pronucleotides: A Comparison of the Phosphoramidase Substrate Specificity of Human and Escherichia coli Histidine Triad Nucleotide Binding Proteins
    Chou, Tsui-Fen; Baraniak, Janina; Kaczmarek, Renata; Zhou, Xin; Cheng, Jilin; Ghosh, Brahma; Wagner, Carston R.
    Molecular Pharmaceutics (2007), 4 (2), 208-217CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    To facilitate the delivery of nucleotide-based therapeutics to cells and tissues, a variety of pronucleotide approaches have been developed. Our lab. and others have demonstrated that nucleoside phosphoramidates can be activated intracellularly to the corresponding 5'-monophosphate nucleotide and that histidine triad nucleotide binding proteins (Hints) are potentially responsible for their bioactivation. Hints are conserved and ubiquitous enzymes that hydrolyze phosphoramidate bonds between nucleoside 5'-monophosphate and an amine leaving group. On the basis of the ability of nucleosides to quench the fluorescence of covalently linked amines contg. indole, a sensitive, continuous fluorescence-based assay was developed. A series of substrates linking the naturally fluorogenic indole derivs. to nucleoside 5'-monophosphates were synthesized, and their steady state kinetic parameters of hydrolysis by human Hint1 and Escherichia coli hinT were evaluated. To characterize the elemental and stereochem. effect on the reaction, two P-diastereoisomers of adenosine or guanosine phosphoramidothioates were synthesized and studied to reveal a 15-200-fold decrease in the specificity const. (kcat/Km) when the phosphoryl oxygen is replaced with sulfur. While a stereochem. preference was not obsd. for E. coli hinT, hHint1 exhibited a 300-fold preference for D-tryptophan phosphoramidates over L-isomers. The most efficient substrates evaluated to date are those that contain the less sterically hindering amine leaving group, tryptamine, with kcat and Km values comparable to those found for adenosine kinase. The apparent second-order rate consts. (kcat/Km) for adenosine tryptamine phosphoramidate monoester were found to be 107 M-1 s-1 for hHint1 and 106 M-1 s-1 for E. coli hinT. Both the human and E. coli enzymes preferred purine over pyrimidine analogs. Consistent with obsd. hydrogen bonding between the 2'-OH group of adenosine monophosphate and the active site residue, Asp43, the second-order rate const. (kcat/Km) for thymidine tryptamine phosphoramidate was found to be 3-4 orders of magnitude smaller than that for uridine tryptamine phosphoramidate for hHint1 and 2 orders of magnitude smaller than that for E. coli hinT. Ara-A tryptamine phosphoramidate was, however, shown to be a good substrate with a specificity const. (kcat/Km) only 10-fold lower than the value for adenosine tryptamine phosphoramidate. Consequently, nucleoside phosphoramidates contg. unhindered primary amines and either an α or β 2'-OH group should be easily bioactivated by Hints with efficiencies rivaling those for the 5'-monophosphorylation of nucleosides by nucleoside kinases. The differential substrate specificity obsd. for human and E. coli enzymes represents a potential therapeutic rationale for the development of selective antibiotic phosphoramidate pronucleotides.
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  12. 12
    Wichmann, D.; Sperhake, J.-P.; Lütgehetmann, M.; Steurer, S.; Edler, C.; Heinemann, A.; Heinrich, F.; Mushumba, H.; Kniep, I.; Schröder, A. S. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19. Ann. Intern. Med. 2020, M20– 2003,  DOI: 10.7326/M20-2003
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    Beigel, J. H.; Tomashek, K. M.; Dodd, L. E.; Mehta, A. K.; Zingman, B. S.; Kalil, A. C.; Hohmann, E.; Chu, H. Y.; Luetkemeyer, A.; Kline, S. Remdesivir for the Treatment of Covid-19 — Preliminary Report. N. Engl. J. Med. 2020,  DOI: 10.1056/NEJMoa2007764
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    There is no corresponding record for this reference.
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    Cooke, A. M.; Baron, D. N. Section of Medicine with Section of Pathology-Serum Enzymes in Clinical Practice ; 1963; Vol. 56.
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    Testa, B.; Mayer, J. M. Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology; VHCA, 2003.
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    Bahar, F. G.; Ohura, K.; Ogihara, T.; Imai, T. Species Difference of Esterase Expression and Hydrolase Activity in Plasma. J. Pharm. Sci. 2012, 101 (10), 3979– 3988,  DOI: 10.1002/jps.23258
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    Species difference of esterase expression and hydrolase activity in plasma
    Bahar, Fatma Goksin; Ohura, Kayoko; Ogihara, Takuo; Imai, Teruko
    Journal of Pharmaceutical Sciences (2012), 101 (10), 3979-3988CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    Differences in esterase expression among human, rhesus monkey, cynomolgus monkey, dog, minipig, rabbit, rat, and mouse plasma were identified using native polyacrylamide gel electrophoresis. Paraoxonase (PON) and butyrylcholinesterase (BChE) were ubiquitous in all species, but were highly expressed in primates and dogs, whereas carboxylesterase (CES) was only abundant in rabbits, mice, and rats. Several unknown esterases were obsd. in minipig and mouse plasma. These differences in plasma esterases and their expression levels result in species differences with respect to hydrolase activity. These differences were characterized using several different substrates. In contrast to the high hydrolase activity found for p-nitrophenylacetate (PNPA), a substrate of several hydrolase enzymes, irinotecan, a carbamate compd., was resistant to all plasma esterases. Oseltamivir, temocapril, and propranolol (PL) derivs. were rapidly hydrolyzed in mouse and rat plasma by their highly active CES enzyme, but rabbit plasma CES hydrolyzed only the PL derivs. Interestingly, PL derivs. were highly hydrolyzed by monkey plasma BChE, whereas BChE from human, dog, and minipig plasma showed negligible activity. In conclusion, the esterase expression and hydrolyzing pattern of dog plasma were found to be closest to that of human plasma. These differences should be considered when selecting model animals for preclin. studies.
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  17. 17
    Yong, J. M. Origins of Serum Alkaline Phosphatase. J. Clin. Pathol. 1967, 20 (4), 647– 653,  DOI: 10.1136/jcp.20.4.647
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    17
    Origins of serum alkaline phosphatase
    Yong, J. M.
    Journal of Clinical Pathology (1967), 20 (4), 647-53CODEN: JCPAAK; ISSN:0021-9746.
    A very rapid method of agar-gel electrophoresis on glass slides patterned after that of Wieme (CA 53: 16231i) was utilized to isolate serum alk. phosphatases (I) which were then visualized by a coupling diazo reaction with a naphthol substrate. When combined with the use of L-phenylalanine, which specifically inhibits I of intestinal origin (Ii), the use of heat to inactivate I of placental origin (Ip), the use of neuraminidase to inhibit the electrophoretic mobility of liver and bone I but not that of Ii, and with comparisons of the electrophoretic mobility relative to serum proteins, it was possible to det. the origin of the various I present in serum. Examn. of serums of 50 normal adults indicated the presence of a single I isoenzyme originating in the liver (II) (or possibly in the lung or blood vessels); in addn. smaller amts. of Ii were found in 3 instances. Serums from healthy children contained II and also I originating in bone (IB). In 1 instance of 30, Ii was also present. The amts. of Ib decreased with age. In pregnancy, Ip increased. Patients with osteoblastic bone lesions showed increased amts. of Ib, while those with hepatobiliary disorders showed increases of Il. Patients in the lastmentioned category who also had assocd. bone disorders or multiorgan disorders such as disseminated cancer also showed increased Ib and Ii.
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    Pruijssers, A. J.; George, A. S.; Schäfer, A.; Leist, S. R.; Gralinksi, L. E.; Dinnon Iii, K. H.; Yount, B. L.; Agostini, M. L.; Stevens, L. J.; Chappell, J. D. Remdesivir Potently Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. bioRxiv 2020,  DOI: 10.1101/2020.04.27.064279
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    Lo, M. K.; Jordan, R.; Arvey, A.; Sudhamsu, J.; Shrivastava-Ranjan, P.; Hotard, A. L.; Flint, M.; McMullan, L. K.; Siegel, D.; Clarke, M. O. GS-5734 and Its Parent Nucleoside Analog Inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci. Rep. 2017, 7 (1), 43395,  DOI: 10.1038/srep43395
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    19
    GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses
    Lo Michael K; Shrivastava-Ranjan Punya; Hotard Anne L; Flint Mike; McMullan Laura K; Nichol Stuart T; Spiropoulou Christina F; Jordan Robert; Arvey Aaron; Sudhamsu Jawahar; Siegel Dustin; Clarke Michael O; Mackman Richard L; Hui Hon C; Perron Michel; Ray Adrian S; Cihlar Tomas
    Scientific reports (2017), 7 (), 43395 ISSN:.
    GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern.
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    Choy, K.-T.; Wong, A. Y.-L.; Kaewpreedee, P.; Sia, S. F.; Chen, D.; Hui, K. P. Y.; Chu, D. K. W.; Chan, M. C. W.; Cheung, P. P.-H.; Huang, X. Remdesivir, Lopinavir, Emetine, and Homoharringtonine Inhibit SARS-CoV-2 Replication in Vitro. Antiviral Res. 2020, 178, 104786,  DOI: 10.1016/j.antiviral.2020.104786
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    20
    Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro
    Choy, Ka-Tim; Wong, Alvina Yin-Lam; Kaewpreedee, Prathanporn; Sia, Sin Fun; Chen, Dongdong; Hui, Kenrie Pui Yan; Chu, Daniel Ka Wing; Chan, Michael Chi Wai; Cheung, Peter Pak-Hang; Huang, Xuhui; Peiris, Malik; Yen, Hui-Ling
    Antiviral Research (2020), 178 (), 104786CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
    An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compds. that were previously reported to inhibit coronavirus replication and compds. that are currently under evaluation in clin. trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estd. 50% effective concn. at 23.15μM, 26.63μM, 2.55μM and 0.46μM, resp. Ribavirin or favipiravir that are currently evaluated under clin. trials showed no inhibition at 100μM. Synergy between remdesivir and emetine was obsd., and remdesivir at 6.25μM in combination with emetine at 0.195μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concn. of compds. below the therapeutic plasma concns. and provide better clin. benefits.
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  21. 21
    Pedersen, N. C.; Perron, M.; Bannasch, M.; Montgomery, E.; Murakami, E.; Liepnieks, M.; Liu, H. Efficacy and Safety of the Nucleoside Analog GS-441524 for Treatment of Cats with Naturally Occurring Feline Infectious Peritoniti. J. Feline Med. Surg. 2019, 21 (4), 271– 281,  DOI: 10.1177/1098612X19825701
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    21
    Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis
    Pedersen Niels C; Bannasch Michael; Montgomery Elizabeth; Perron Michel; Murakami Eisuke; Liepnieks Molly; Liu Hongwei
    Journal of feline medicine and surgery (2019), 21 (4), 271-281 ISSN:.
    OBJECTIVES: The aim of this study was to determine the safety and efficacy of the nucleoside analog GS-441524 for cats suffering from various forms of naturally acquired feline infectious peritonitis (FIP). METHODS: Cats ranged from 3.4-73 months of age (mean 13.6 months); 26 had effusive or dry-to-effusive FIP and five had non-effusive disease. Cats with severe neurological and ocular FIP were not recruited. The group was started on GS-441524 at a dosage of 2.0 mg/kg SC q24h for at least 12 weeks and increased when indicated to 4.0 mg/kg SC q24h. RESULTS: Four of the 31 cats that presented with severe disease died or were euthanized within 2-5 days and a fifth cat after 26 days. The 26 remaining cats completed the planned 12 weeks or more of treatment. Eighteen of these 26 cats remain healthy at the time of publication (OnlineFirst, February 2019) after one round of treatment, while eight others suffered disease relapses within 3-84 days. Six of the relapses were non-neurological and two neurological. Three of the eight relapsing cats were treated again at the same dosage, while five cats had the dosage increased from 2.0 to 4.0 mg/kg q24h. The five cats treated a second time at the higher dosage, including one with neurological disease, responded well and also remain healthy at the time of publication. However, one of the three cats re-treated at the original lower dosage relapsed with neurological disease and was euthanized, while the two remaining cats responded favorably but relapsed a second time. These two cats were successfully treated a third time at the higher dosage, producing 25 long-time survivors. One of the 25 successfully treated cats was subsequently euthanized due to presumably unrelated heart disease, while 24 remain healthy. CONCLUSIONS AND RELEVANCE: GS-441524 was shown to be a safe and effective treatment for FIP. The optimum dosage was found to be 4.0 mg/kg SC q24h for at least 12 weeks.
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  22. 22
    Murphy, B. G.; Perron, M.; Murakami, E.; Bauer, K.; Park, Y.; Eckstrand, C.; Liepnieks, M.; Pedersen, N. C. The Nucleoside Analog GS-441524 Strongly Inhibits Feline Infectious Peritonitis (FIP) Virus in Tissue Culture and Experimental Cat Infection Studies. Vet. Microbiol. 2018, 219, 226– 233,  DOI: 10.1016/j.vetmic.2018.04.026
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    22
    The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies
    Murphy, B. G.; Perron, M.; Murakami, E.; Bauer, K.; Park, Y.; Eckstrand, C.; Liepnieks, M.; Pedersen, N. C.
    Veterinary Microbiology (2018), 219 (), 226-233CODEN: VMICDQ; ISSN:0378-1135. (Elsevier B.V.)
    Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small mol. nucleoside analog GS-441524 is a mol. precursor to a pharmacol. active nucleoside triphosphate mol. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We detd. that GS-441524 was non-toxic in feline cells at concns. as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concns. as low as 1 uM. We detd. the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an exptl. FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.
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  23. 23
    Dickinson, P. J.; Bannasch, M.; Thomasy, S. M.; Murthy, V. D.; Vernau, K. M.; Liepnieks, M.; Montgomery, E.; Knickelbein, K. E.; Murphy, B.; Pedersen, N. C. Antiviral Treatment Using the Adenosine Nucleoside Analogue GS −441524 in Cats with Clinically Diagnosed Neurological Feline Infectious Peritonitis. J. Vet. Intern. Med. 2020,  DOI: 10.1111/jvim.15780
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    Addie, D.; Belák, S.; Boucraut-Baralon, C.; Egberink, H.; Frymus, T.; Gruffydd-Jones, T.; Hartmann, K.; Hosie, M. J.; Lloret, A.; Lutz, H. Feline Infectious Peritonitis. ABCD Guidelines on Prevention and Management. J. Feline Med. Surg. 2009, 11 (7), 594– 604,  DOI: 10.1016/j.jfms.2009.05.008
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    24
    Feline infectious peritonitis. ABCD guidelines on prevention and management
    Addie Diane; Belak Sandor; Boucraut-Baralon Corine; Egberink Herman; Frymus Tadeusz; Gruffydd-Jones Tim; Hartmann Katrin; Hosie Margaret J; Lloret Albert; Lutz Hans; Marsilio Fulvio; Pennisi Maria Grazia; Radford Alan D; Thiry Etienne; Truyen Uwe; Horzinek Marian C
    Journal of feline medicine and surgery (2009), 11 (7), 594-604 ISSN:1098-612X.
    OVERVIEW: Feline coronavirus infection is ubiquitous in domestic cats, and is particularly common where conditions are crowded. While most FCoV-infected cats are healthy or display only a mild enteritis, some go on to develop feline infectious peritonitis, a disease that is especially common in young cats and multi-cat environments. Up to 12% of FCoV-infected cats may succumb to FIP, with stress predisposing to the development of disease. DISEASE SIGNS: The 'wet' or effusive form, characterised by polyserositis (abdominal and/or thoracic effusion) and vasculitis, and the 'dry' or non-effusive form (pyogranulomatous lesions in organs) reflect clinical extremes of a continuum. The clinical picture of FIP is highly variable, depending on the distribution of the vasculitis and pyogranulomatous lesions. Fever refractory to antibiotics, lethargy, anorexia and weight loss are common non-specific signs. Ascites is the most obvious manifestation of the effusive form. DIAGNOSIS: The aetiological diagnosis of FIP ante-mortem may be difficult, if not impossible. The background of the cat, its history, the clinical signs, laboratory changes, antibody titres and effusion analysis should all be used to help in decision-making about further diagnostic procedures. At the time of writing, there is no non-invasive confirmatory test available for cats without effusion. DISEASE MANAGEMENT: In most cases FIP is fatal. Supportive treatment is aimed at suppressing the inflammatory and detrimental immune response. However, there are no controlled studies to prove any beneficial effect of corticosteroids. VACCINATION RECOMMENDATIONS: At present, only one (intranasal) FIP vaccine is available, which is considered as being non-core. Kittens may profit from vaccination when they have not been exposed to FCoV (eg, in an early-weaning programme), particularly if they enter a FCoV-endemic environment.
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    Wang, Y.; Zhang, D.; Du, G.; Du, R.; Zhao, J.; Jin, Y.; Fu, S.; Gao, L.; Cheng, Z.; Lu, Q. Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial. Lancet 2020, 395 (10236), 1569– 1578,  DOI: 10.1016/S0140-6736(20)31022-9
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    25
    Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
    Wang, Yeming; Zhang, Dingyu; Du, Guanhua; Du, Ronghui; Zhao, Jianping; Jin, Yang; Fu, Shouzhi; Gao, Ling; Cheng, Zhenshun; Lu, Qiaofa; Hu, Yi; Luo, Guangwei; Wang, Ke; Lu, Yang; Li, Huadong; Wang, Shuzhen; Ruan, Shunan; Yang, Chengqing; Mei, Chunlin; Wang, Yi; Ding, Dan; Wu, Feng; Tang, Xin; Ye, Xianzhi; Ye, Yingchun; Liu, Bing; Yang, Jie; Yin, Wen; Wang, Aili; Fan, Guohui; Zhou, Fei; Liu, Zhibo; Gu, Xiaoying; Xu, Jiuyang; Shang, Lianhan; Zhang, Yi; Cao, Lianjun; Guo, Tingting; Wan, Yan; Qin, Hong; Jiang, Yushen; Jaki, Thomas; Hayden, Frederick G.; Horby, Peter W.; Cao, Bin; Wang, Chen
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  • Abstract

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    Figure 1

    Figure 1. McGuigan prodrugs on remdesivir are prematurely hydrolyzed in serum. (A) The ideal bioactivation of remdesivir predominately occurs in vitro. (B) The presence of serum enzymes in vivo predominately results in premature hydrolysis of the phosphate prodrugs, followed by dephosphorylation to the nucleoside, GS-441524.

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    Figure 2

    Figure 2. McGuigan prodrugs on remdesivir are preferentially bioactivated in the liver. (A) Labile prodrug moieties on remdesivir with corresponding bioactivation enzymes. (B) Relative tissue mRNA expression of initial prodrug bioactivating enzymes for RDV (CES1/CTSA/HINT1) adapted from the HPA data set on the Human Protein Atlas reported as median-centered protein-coding transcripts per million (pTPM). Overall, McGuigan prodrug bioactivating enzymes are more highly expressed in the liver than in the lungs. (C) Immunohistochemistry images from the Human Protein Atlas indicating expression for ProTide bioactivating enzymes. Brown regions indicate enzyme expression while blue regions indicate absent expression. For the lung, pneumocytes—cells frequently infected by Covid-19—are characterized by a threadlike appearance. Expression in the liver is generally higher compared to lung for all enzymes. For CTSA, darkly stained regions are associated with macrophages. IHC images for the skin are included to show lack of enzyme expression. Antibodies used: CTSA (CAB024930), CES1 (HPA046717), HINT1 (HPA044577).

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    Figure 3

    Figure 3. Unlike remdesivir, GS-441524 persists in serum at concentrations above the EC50 value required against SARS-CoV-infected primary HAE cells for long durations. (A) In vitro potency data replotted from Agostini et al. mBio, 2018. (2) Primary HAE cells were infected with either MERS-CoV or SARS-CoV and treated with either GS-441524 (open squares) or remdesivir (closed circles). Mean EC50 of GS-441524 for SARS-CoV-infected HAE cells was found to be 0.18 ± 0.14 μM (note large standard deviations, red arrows). A study by Murphy et al. shows that GS-441524 has an EC50 value of 0.78 μM against FCoV-infected CRFK cells (red dashed line), (22) which is higher than the EC50 value for GS-441524 against SARS-CoV-infected primary HAE cells. (B) Estimated metabolite concentrations for a PK experiment in a SARS-CoV-2 primate model replotted from Williamson et al. Nature, 2020. (6) Primates were initially injected IV with 10 mg/kg of remdesivir 12 h postinoculation with SARS-CoV-2 and then 5 mg/kg of remdesivir every 24 h after. Throughout the experiment, GS-441524 is present in serum at concentrations ∼1000-fold higher than remdesivir; the concentration of GS-441524 is consistently above the EC50 value in SARS-CoV-infected primary HAE cells (red dashed line) at all time points taken in the experiment. In contrast, the concentration of remdesivir in serum never exceeds that required to give the EC50 value against SARS-CoV-infected primary HAE cells (gray dashed line). (C) PK data replotted from Warren et al. Nature, 2016 (3) following IV injection (10 mg/kg) of remdesivir in NHP. Dashed lines indicate the approximate EC50 values of GS-441524 (red) or remdesivir (gray) needed to reach EC50 in SARS-CoV primary HAE cells obtained in (A). Unlike remdesivir, the concentration of drug required to give the EC50 value against SARS-CoV primary HAE cells is maintained for significantly longer with GS-441524 than with remdesivir.

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      Gordon, Calvin J.; Tchesnokov, Egor P.; Feng, Joy Y.; Porter, Danielle P.; Gotte, Matthias
      Journal of Biological Chemistry (2020), 295 (15), 4773-4779CODEN: JBCHA3; ISSN:1083-351X. (American Society for Biochemistry and Molecular Biology)
      Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at contg. the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compd. with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained with a steady-state approach suggests that it is more efficiently incorporated than ATP and 2 other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The addnl. 3 nucleotides may protect the inhibitor from excision by the viral 3'-5' exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.
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    8. 8
      Alanazi, A. S.; James, E.; Mehellou, Y. The ProTide Prodrug Technology: Where Next?. ACS Med. Chem. Lett. 2019, 10 (1), 2– 5,  DOI: 10.1021/acsmedchemlett.8b00586
      8
      The ProTide prodrug technology: Where next?
      Alanazi, Ashwag S.; James, Edward; Mehellou, Youcef
      ACS Medicinal Chemistry Letters (2019), 10 (1), 2-5CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      A review. The ProTide prodrug technol. has proved very useful in the discovery of nucleotide therapeutics and has successfully led to two FDA-approved drugs. However, with the extensive application of this prodrug approach to nucleotides for nearly three decades, the intellectual property (IP) landscape is becoming congested and, to overcome this, new inventive applications of the ProTide prodrug technol. are emerging.
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    9. 9
      Murakami, E.; Wang, T.; Babusis, D.; Lepist, E.-I.; Sauer, D.; Park, Y.; Vela, J. E.; Shih, R.; Birkus, G.; Stefanidis, D. Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620 Downloaded From. Antimicrob. Agents Chemother. 2014, 58, 1943– 1951,  DOI: 10.1128/AAC.02350-13
      9
      Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620
      Murakami, Eisuke; Wang, Ting; Babusis, Darius; Lepist, Eve-Irene; Sauer, Dorothea; Park, Yeojin; Vela, Jennifer E.; Shih, Robert; Birkus, Gabriel; Stefanidis, Dimitrios; Kim, Choung U.; Cho, Aesop; Ray, Adrian S.
      Antimicrobial Agents and Chemotherapy (2014), 58 (4), 1943-1951, 10 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-iso-Pr ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equiv. surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be crit. to the effectiveness of GS-6620 in nonclin. species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concn. Higher rates of metab. were obsd. at lower concns. that were unable to sat. intestinal efflux transporters. In first-in-human clin. trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that obsd. in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3'-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metab. and relatively poor oral absorption in humans.
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    10. 10
      Bieganowski, P.; Garrison, P. N.; Hodawadekar, S. C.; Faye, G.; Barnes, L. D.; Brenner, C. Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3. J. Biol. Chem. 2002, 277 (13), 10852– 10860,  DOI: 10.1074/jbc.M111480200
      10
      Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3
      Bieganowski, Pawel; Garrison, Preston N.; Hodawadekar, Santosh C.; Faye, Gerard; Barnes, Larry D.; Brenner, Charles
      Journal of Biological Chemistry (2002), 277 (13), 10852-10860CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      The histidine triad superfamily of nucleotide hydrolases and nucleotide transferases consists of a branch of proteins related to Hint and Aprataxin, a branch of Fhit-related hydrolases, and a branch of galactose-1-phosphate uridylytransferase (GalT)-related transferases. Although substrates of Fhit and GalT are known and consequences of mutations in Aprataxin, Fhit, and GalT are known, good substrates had not been reported for any member of the Hint branch, and mutational consequences were unknown for Hint orthologs, which are the most ancient and widespread proteins in the Hint branch and in the histidine triad superfamily. Here we show that rabbit and yeast Hint hydrolyze the natural product adenosine-5'-monophosphoramidate (AMPNH2) in an active-site-dependent manner at second order rates exceeding 1,000,000 M-1 S-1. Yeast strains constructed with specific loss of the Hnt1 active site fail to grow on galactose at elevated temps. Loss of Hnt1 enzyme activity also leads to hypersensitivity to mutations in Ccl1, Tfb3, and Kin28, which constitute the TFIIK kinase subcomplex of general transcription factor TFIIH and to mutations in Cak1, which phosphorylates Kin28. The target of Hnt1 regulation in this pathway was shown to be downstream of Cak1 and not to affect stability of Kin28 monomers. Functional complementation of all Hnt1 phenotypes was provided by rabbit Hint, which is only 22% identical to yeast Hnt1 but has very similar adenosine monophosphoramidase activity.
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    11. 11
      Chou, T.-F.; Baraniak, J.; Kaczmarek, R.; Zhou, X.; Cheng, J.; Ghosh, B.; Wagner, C. R. Phosphoramidate Pronucleotides: A Comparison of the Phosphoramidase Substrate Specificity of Human and Escherichia Coli Histidine Triad Nucleotide Binding Proteins. Mol. Pharmaceutics 2007, 4 (2), 208– 217,  DOI: 10.1021/mp060070y
      11
      Phosphoramidate Pronucleotides: A Comparison of the Phosphoramidase Substrate Specificity of Human and Escherichia coli Histidine Triad Nucleotide Binding Proteins
      Chou, Tsui-Fen; Baraniak, Janina; Kaczmarek, Renata; Zhou, Xin; Cheng, Jilin; Ghosh, Brahma; Wagner, Carston R.
      Molecular Pharmaceutics (2007), 4 (2), 208-217CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      To facilitate the delivery of nucleotide-based therapeutics to cells and tissues, a variety of pronucleotide approaches have been developed. Our lab. and others have demonstrated that nucleoside phosphoramidates can be activated intracellularly to the corresponding 5'-monophosphate nucleotide and that histidine triad nucleotide binding proteins (Hints) are potentially responsible for their bioactivation. Hints are conserved and ubiquitous enzymes that hydrolyze phosphoramidate bonds between nucleoside 5'-monophosphate and an amine leaving group. On the basis of the ability of nucleosides to quench the fluorescence of covalently linked amines contg. indole, a sensitive, continuous fluorescence-based assay was developed. A series of substrates linking the naturally fluorogenic indole derivs. to nucleoside 5'-monophosphates were synthesized, and their steady state kinetic parameters of hydrolysis by human Hint1 and Escherichia coli hinT were evaluated. To characterize the elemental and stereochem. effect on the reaction, two P-diastereoisomers of adenosine or guanosine phosphoramidothioates were synthesized and studied to reveal a 15-200-fold decrease in the specificity const. (kcat/Km) when the phosphoryl oxygen is replaced with sulfur. While a stereochem. preference was not obsd. for E. coli hinT, hHint1 exhibited a 300-fold preference for D-tryptophan phosphoramidates over L-isomers. The most efficient substrates evaluated to date are those that contain the less sterically hindering amine leaving group, tryptamine, with kcat and Km values comparable to those found for adenosine kinase. The apparent second-order rate consts. (kcat/Km) for adenosine tryptamine phosphoramidate monoester were found to be 107 M-1 s-1 for hHint1 and 106 M-1 s-1 for E. coli hinT. Both the human and E. coli enzymes preferred purine over pyrimidine analogs. Consistent with obsd. hydrogen bonding between the 2'-OH group of adenosine monophosphate and the active site residue, Asp43, the second-order rate const. (kcat/Km) for thymidine tryptamine phosphoramidate was found to be 3-4 orders of magnitude smaller than that for uridine tryptamine phosphoramidate for hHint1 and 2 orders of magnitude smaller than that for E. coli hinT. Ara-A tryptamine phosphoramidate was, however, shown to be a good substrate with a specificity const. (kcat/Km) only 10-fold lower than the value for adenosine tryptamine phosphoramidate. Consequently, nucleoside phosphoramidates contg. unhindered primary amines and either an α or β 2'-OH group should be easily bioactivated by Hints with efficiencies rivaling those for the 5'-monophosphorylation of nucleosides by nucleoside kinases. The differential substrate specificity obsd. for human and E. coli enzymes represents a potential therapeutic rationale for the development of selective antibiotic phosphoramidate pronucleotides.
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    12. 12
      Wichmann, D.; Sperhake, J.-P.; Lütgehetmann, M.; Steurer, S.; Edler, C.; Heinemann, A.; Heinrich, F.; Mushumba, H.; Kniep, I.; Schröder, A. S. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19. Ann. Intern. Med. 2020, M20– 2003,  DOI: 10.7326/M20-2003
      There is no corresponding record for this reference.
    13. 13
      Beigel, J. H.; Tomashek, K. M.; Dodd, L. E.; Mehta, A. K.; Zingman, B. S.; Kalil, A. C.; Hohmann, E.; Chu, H. Y.; Luetkemeyer, A.; Kline, S. Remdesivir for the Treatment of Covid-19 — Preliminary Report. N. Engl. J. Med. 2020,  DOI: 10.1056/NEJMoa2007764
      There is no corresponding record for this reference.
    14. 14
      Cooke, A. M.; Baron, D. N. Section of Medicine with Section of Pathology-Serum Enzymes in Clinical Practice ; 1963; Vol. 56.
      There is no corresponding record for this reference.
    15. 15
      Testa, B.; Mayer, J. M. Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology; VHCA, 2003.
      There is no corresponding record for this reference.
    16. 16
      Bahar, F. G.; Ohura, K.; Ogihara, T.; Imai, T. Species Difference of Esterase Expression and Hydrolase Activity in Plasma. J. Pharm. Sci. 2012, 101 (10), 3979– 3988,  DOI: 10.1002/jps.23258
      16
      Species difference of esterase expression and hydrolase activity in plasma
      Bahar, Fatma Goksin; Ohura, Kayoko; Ogihara, Takuo; Imai, Teruko
      Journal of Pharmaceutical Sciences (2012), 101 (10), 3979-3988CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
      Differences in esterase expression among human, rhesus monkey, cynomolgus monkey, dog, minipig, rabbit, rat, and mouse plasma were identified using native polyacrylamide gel electrophoresis. Paraoxonase (PON) and butyrylcholinesterase (BChE) were ubiquitous in all species, but were highly expressed in primates and dogs, whereas carboxylesterase (CES) was only abundant in rabbits, mice, and rats. Several unknown esterases were obsd. in minipig and mouse plasma. These differences in plasma esterases and their expression levels result in species differences with respect to hydrolase activity. These differences were characterized using several different substrates. In contrast to the high hydrolase activity found for p-nitrophenylacetate (PNPA), a substrate of several hydrolase enzymes, irinotecan, a carbamate compd., was resistant to all plasma esterases. Oseltamivir, temocapril, and propranolol (PL) derivs. were rapidly hydrolyzed in mouse and rat plasma by their highly active CES enzyme, but rabbit plasma CES hydrolyzed only the PL derivs. Interestingly, PL derivs. were highly hydrolyzed by monkey plasma BChE, whereas BChE from human, dog, and minipig plasma showed negligible activity. In conclusion, the esterase expression and hydrolyzing pattern of dog plasma were found to be closest to that of human plasma. These differences should be considered when selecting model animals for preclin. studies.
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    17. 17
      Yong, J. M. Origins of Serum Alkaline Phosphatase. J. Clin. Pathol. 1967, 20 (4), 647– 653,  DOI: 10.1136/jcp.20.4.647
      17
      Origins of serum alkaline phosphatase
      Yong, J. M.
      Journal of Clinical Pathology (1967), 20 (4), 647-53CODEN: JCPAAK; ISSN:0021-9746.
      A very rapid method of agar-gel electrophoresis on glass slides patterned after that of Wieme (CA 53: 16231i) was utilized to isolate serum alk. phosphatases (I) which were then visualized by a coupling diazo reaction with a naphthol substrate. When combined with the use of L-phenylalanine, which specifically inhibits I of intestinal origin (Ii), the use of heat to inactivate I of placental origin (Ip), the use of neuraminidase to inhibit the electrophoretic mobility of liver and bone I but not that of Ii, and with comparisons of the electrophoretic mobility relative to serum proteins, it was possible to det. the origin of the various I present in serum. Examn. of serums of 50 normal adults indicated the presence of a single I isoenzyme originating in the liver (II) (or possibly in the lung or blood vessels); in addn. smaller amts. of Ii were found in 3 instances. Serums from healthy children contained II and also I originating in bone (IB). In 1 instance of 30, Ii was also present. The amts. of Ib decreased with age. In pregnancy, Ip increased. Patients with osteoblastic bone lesions showed increased amts. of Ib, while those with hepatobiliary disorders showed increases of Il. Patients in the lastmentioned category who also had assocd. bone disorders or multiorgan disorders such as disseminated cancer also showed increased Ib and Ii.
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    18. 18
      Pruijssers, A. J.; George, A. S.; Schäfer, A.; Leist, S. R.; Gralinksi, L. E.; Dinnon Iii, K. H.; Yount, B. L.; Agostini, M. L.; Stevens, L. J.; Chappell, J. D. Remdesivir Potently Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. bioRxiv 2020,  DOI: 10.1101/2020.04.27.064279
      There is no corresponding record for this reference.
    19. 19
      Lo, M. K.; Jordan, R.; Arvey, A.; Sudhamsu, J.; Shrivastava-Ranjan, P.; Hotard, A. L.; Flint, M.; McMullan, L. K.; Siegel, D.; Clarke, M. O. GS-5734 and Its Parent Nucleoside Analog Inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci. Rep. 2017, 7 (1), 43395,  DOI: 10.1038/srep43395
      19
      GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses
      Lo Michael K; Shrivastava-Ranjan Punya; Hotard Anne L; Flint Mike; McMullan Laura K; Nichol Stuart T; Spiropoulou Christina F; Jordan Robert; Arvey Aaron; Sudhamsu Jawahar; Siegel Dustin; Clarke Michael O; Mackman Richard L; Hui Hon C; Perron Michel; Ray Adrian S; Cihlar Tomas
      Scientific reports (2017), 7 (), 43395 ISSN:.
      GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern.
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    20. 20
      Choy, K.-T.; Wong, A. Y.-L.; Kaewpreedee, P.; Sia, S. F.; Chen, D.; Hui, K. P. Y.; Chu, D. K. W.; Chan, M. C. W.; Cheung, P. P.-H.; Huang, X. Remdesivir, Lopinavir, Emetine, and Homoharringtonine Inhibit SARS-CoV-2 Replication in Vitro. Antiviral Res. 2020, 178, 104786,  DOI: 10.1016/j.antiviral.2020.104786
      20
      Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro
      Choy, Ka-Tim; Wong, Alvina Yin-Lam; Kaewpreedee, Prathanporn; Sia, Sin Fun; Chen, Dongdong; Hui, Kenrie Pui Yan; Chu, Daniel Ka Wing; Chan, Michael Chi Wai; Cheung, Peter Pak-Hang; Huang, Xuhui; Peiris, Malik; Yen, Hui-Ling
      Antiviral Research (2020), 178 (), 104786CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
      An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compds. that were previously reported to inhibit coronavirus replication and compds. that are currently under evaluation in clin. trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estd. 50% effective concn. at 23.15μM, 26.63μM, 2.55μM and 0.46μM, resp. Ribavirin or favipiravir that are currently evaluated under clin. trials showed no inhibition at 100μM. Synergy between remdesivir and emetine was obsd., and remdesivir at 6.25μM in combination with emetine at 0.195μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concn. of compds. below the therapeutic plasma concns. and provide better clin. benefits.
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    21. 21
      Pedersen, N. C.; Perron, M.; Bannasch, M.; Montgomery, E.; Murakami, E.; Liepnieks, M.; Liu, H. Efficacy and Safety of the Nucleoside Analog GS-441524 for Treatment of Cats with Naturally Occurring Feline Infectious Peritoniti. J. Feline Med. Surg. 2019, 21 (4), 271– 281,  DOI: 10.1177/1098612X19825701
      21
      Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis
      Pedersen Niels C; Bannasch Michael; Montgomery Elizabeth; Perron Michel; Murakami Eisuke; Liepnieks Molly; Liu Hongwei
      Journal of feline medicine and surgery (2019), 21 (4), 271-281 ISSN:.
      OBJECTIVES: The aim of this study was to determine the safety and efficacy of the nucleoside analog GS-441524 for cats suffering from various forms of naturally acquired feline infectious peritonitis (FIP). METHODS: Cats ranged from 3.4-73 months of age (mean 13.6 months); 26 had effusive or dry-to-effusive FIP and five had non-effusive disease. Cats with severe neurological and ocular FIP were not recruited. The group was started on GS-441524 at a dosage of 2.0 mg/kg SC q24h for at least 12 weeks and increased when indicated to 4.0 mg/kg SC q24h. RESULTS: Four of the 31 cats that presented with severe disease died or were euthanized within 2-5 days and a fifth cat after 26 days. The 26 remaining cats completed the planned 12 weeks or more of treatment. Eighteen of these 26 cats remain healthy at the time of publication (OnlineFirst, February 2019) after one round of treatment, while eight others suffered disease relapses within 3-84 days. Six of the relapses were non-neurological and two neurological. Three of the eight relapsing cats were treated again at the same dosage, while five cats had the dosage increased from 2.0 to 4.0 mg/kg q24h. The five cats treated a second time at the higher dosage, including one with neurological disease, responded well and also remain healthy at the time of publication. However, one of the three cats re-treated at the original lower dosage relapsed with neurological disease and was euthanized, while the two remaining cats responded favorably but relapsed a second time. These two cats were successfully treated a third time at the higher dosage, producing 25 long-time survivors. One of the 25 successfully treated cats was subsequently euthanized due to presumably unrelated heart disease, while 24 remain healthy. CONCLUSIONS AND RELEVANCE: GS-441524 was shown to be a safe and effective treatment for FIP. The optimum dosage was found to be 4.0 mg/kg SC q24h for at least 12 weeks.
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    22. 22
      Murphy, B. G.; Perron, M.; Murakami, E.; Bauer, K.; Park, Y.; Eckstrand, C.; Liepnieks, M.; Pedersen, N. C. The Nucleoside Analog GS-441524 Strongly Inhibits Feline Infectious Peritonitis (FIP) Virus in Tissue Culture and Experimental Cat Infection Studies. Vet. Microbiol. 2018, 219, 226– 233,  DOI: 10.1016/j.vetmic.2018.04.026
      22
      The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies
      Murphy, B. G.; Perron, M.; Murakami, E.; Bauer, K.; Park, Y.; Eckstrand, C.; Liepnieks, M.; Pedersen, N. C.
      Veterinary Microbiology (2018), 219 (), 226-233CODEN: VMICDQ; ISSN:0378-1135. (Elsevier B.V.)
      Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small mol. nucleoside analog GS-441524 is a mol. precursor to a pharmacol. active nucleoside triphosphate mol. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We detd. that GS-441524 was non-toxic in feline cells at concns. as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concns. as low as 1 uM. We detd. the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an exptl. FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.
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    23. 23
      Dickinson, P. J.; Bannasch, M.; Thomasy, S. M.; Murthy, V. D.; Vernau, K. M.; Liepnieks, M.; Montgomery, E.; Knickelbein, K. E.; Murphy, B.; Pedersen, N. C. Antiviral Treatment Using the Adenosine Nucleoside Analogue GS −441524 in Cats with Clinically Diagnosed Neurological Feline Infectious Peritonitis. J. Vet. Intern. Med. 2020,  DOI: 10.1111/jvim.15780
      There is no corresponding record for this reference.
    24. 24
      Addie, D.; Belák, S.; Boucraut-Baralon, C.; Egberink, H.; Frymus, T.; Gruffydd-Jones, T.; Hartmann, K.; Hosie, M. J.; Lloret, A.; Lutz, H. Feline Infectious Peritonitis. ABCD Guidelines on Prevention and Management. J. Feline Med. Surg. 2009, 11 (7), 594– 604,  DOI: 10.1016/j.jfms.2009.05.008
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      Feline infectious peritonitis. ABCD guidelines on prevention and management
      Addie Diane; Belak Sandor; Boucraut-Baralon Corine; Egberink Herman; Frymus Tadeusz; Gruffydd-Jones Tim; Hartmann Katrin; Hosie Margaret J; Lloret Albert; Lutz Hans; Marsilio Fulvio; Pennisi Maria Grazia; Radford Alan D; Thiry Etienne; Truyen Uwe; Horzinek Marian C
      Journal of feline medicine and surgery (2009), 11 (7), 594-604 ISSN:1098-612X.
      OVERVIEW: Feline coronavirus infection is ubiquitous in domestic cats, and is particularly common where conditions are crowded. While most FCoV-infected cats are healthy or display only a mild enteritis, some go on to develop feline infectious peritonitis, a disease that is especially common in young cats and multi-cat environments. Up to 12% of FCoV-infected cats may succumb to FIP, with stress predisposing to the development of disease. DISEASE SIGNS: The 'wet' or effusive form, characterised by polyserositis (abdominal and/or thoracic effusion) and vasculitis, and the 'dry' or non-effusive form (pyogranulomatous lesions in organs) reflect clinical extremes of a continuum. The clinical picture of FIP is highly variable, depending on the distribution of the vasculitis and pyogranulomatous lesions. Fever refractory to antibiotics, lethargy, anorexia and weight loss are common non-specific signs. Ascites is the most obvious manifestation of the effusive form. DIAGNOSIS: The aetiological diagnosis of FIP ante-mortem may be difficult, if not impossible. The background of the cat, its history, the clinical signs, laboratory changes, antibody titres and effusion analysis should all be used to help in decision-making about further diagnostic procedures. At the time of writing, there is no non-invasive confirmatory test available for cats without effusion. DISEASE MANAGEMENT: In most cases FIP is fatal. Supportive treatment is aimed at suppressing the inflammatory and detrimental immune response. However, there are no controlled studies to prove any beneficial effect of corticosteroids. VACCINATION RECOMMENDATIONS: At present, only one (intranasal) FIP vaccine is available, which is considered as being non-core. Kittens may profit from vaccination when they have not been exposed to FCoV (eg, in an early-weaning programme), particularly if they enter a FCoV-endemic environment.
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    25. 25
      Wang, Y.; Zhang, D.; Du, G.; Du, R.; Zhao, J.; Jin, Y.; Fu, S.; Gao, L.; Cheng, Z.; Lu, Q. Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial. Lancet 2020, 395 (10236), 1569– 1578,  DOI: 10.1016/S0140-6736(20)31022-9
      25
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
      Wang, Yeming; Zhang, Dingyu; Du, Guanhua; Du, Ronghui; Zhao, Jianping; Jin, Yang; Fu, Shouzhi; Gao, Ling; Cheng, Zhenshun; Lu, Qiaofa; Hu, Yi; Luo, Guangwei; Wang, Ke; Lu, Yang; Li, Huadong; Wang, Shuzhen; Ruan, Shunan; Yang, Chengqing; Mei, Chunlin; Wang, Yi; Ding, Dan; Wu, Feng; Tang, Xin; Ye, Xianzhi; Ye, Yingchun; Liu, Bing; Yang, Jie; Yin, Wen; Wang, Aili; Fan, Guohui; Zhou, Fei; Liu, Zhibo; Gu, Xiaoying; Xu, Jiuyang; Shang, Lianhan; Zhang, Yi; Cao, Lianjun; Guo, Tingting; Wan, Yan; Qin, Hong; Jiang, Yushen; Jaki, Thomas; Hayden, Frederick G.; Horby, Peter W.; Cao, Bin; Wang, Chen
      Lancet (2020), 395 (10236), 1569-1578CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analog prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. We did a randomized, double-blind, placebo-controlled, multicenter trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with lab.-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrollment of 12 days or less, oxygen satn. of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiol. confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to i.v. remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same vol. of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clin. improvement up to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clin. status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary anal. was done in the intention-to-treat (ITT) population and safety anal. was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomization was not included in the ITT population. Remdesivir use was not assocd. with a difference in time to clin. improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clin. improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients vs. 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients vs. four (5%) patients who stopped placebo early. In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not assocd. with statistically significant clin. benefits. However, the numerical redn. in time to clin. improvement in those treated earlier requires confirmation in larger studies. Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technol. Project.
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    26. 26
      Murphy, B. G.; Perron, M.; Murakami, E.; Bauer, K.; Park, Y.; Eckstrand, C.; Liepnieks, M.; Pedersen, N. C. The Nucleoside Analog GS-441524 Strongly Inhibits Feline Infectiousperitonitis (FIP) Virus in Tissue Culture and Experimental Cat Infection Studies. Vet. Microbiol. 2018, 219, 226– 233,  DOI: 10.1016/j.vetmic.2018.04.026
      26
      The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies
      Murphy, B. G.; Perron, M.; Murakami, E.; Bauer, K.; Park, Y.; Eckstrand, C.; Liepnieks, M.; Pedersen, N. C.
      Veterinary Microbiology (2018), 219 (), 226-233CODEN: VMICDQ; ISSN:0378-1135. (Elsevier B.V.)
      Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small mol. nucleoside analog GS-441524 is a mol. precursor to a pharmacol. active nucleoside triphosphate mol. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We detd. that GS-441524 was non-toxic in feline cells at concns. as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concns. as low as 1 uM. We detd. the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an exptl. FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpsFygtL8%253D&md5=e5a8ed119e06599a8ad939ae08408c59
    27. 27
      Agostini, M. L.; Andres, E. L.; Sims, A. C.; Graham, R. L.; Sheahan, T. P.; Lu, X.; Clinton Smith, E.; Brett Case, J.; Feng, J. Y.; Jordan, R. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease Downloaded From. mBio 2018, 9 (2), ee00221– 18,  DOI: 10.1128/mBio.00221-18
      There is no corresponding record for this reference.
    28. 28
      Jarvis, L. M. Scaling up Remdesivir amid the Coronavirus Crisis. C&EN . April 20, 2020.
      There is no corresponding record for this reference.
    29. 29
      Williamson, B. N.; Feldmann, F.; Schwarz, B.; Meade-White, K.; Porter, D. P.; Schulz, J.; Doremalen, N.; van Leighton, I.; Yinda, C. K.; Pérez-Pérez, L. Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2. bioRxiv 2020, 2020.04.15.043166
      There is no corresponding record for this reference.
    30. 30
      Cho, A.; Saunders, O. L.; Butler, T.; Zhang, L.; Xu, J.; Vela, J. E.; Feng, J. Y.; Ray, A. S.; Kim, C. U. Synthesis and Antiviral Activity of a Series of 1′-Substituted 4-Aza-7,9-Dideazaadenosine C-Nucleosides. Bioorg. Med. Chem. Lett. 2012, 22 (8), 2705– 2707,  DOI: 10.1016/j.bmcl.2012.02.105
      30
      Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides
      Cho, Aesop; Saunders, Oliver L.; Butler, Thomas; Zhang, Lijun; Xu, Jie; Vela, Jennifer E.; Feng, Joy Y.; Ray, Adrian S.; Kim, Choung U.
      Bioorganic & Medicinal Chemistry Letters (2012), 22 (8), 2705-2707CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A series of 1'-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside, e.g. I, were prepd. and evaluated for the potential as antiviral agents. These compds. showed a broad range of inhibitory activity against various RNA viruses. In particular, the whole cell potency against HCV when R = CN was attributed to inhibition of HCV NS5B polymerase and intracellular concn. of the corresponding nucleoside triphosphate.
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