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Design and investigation of interactions of novel peptide conjugates of purine and pyrimidine derivatives with EGFR and its mutant T790M/L858R: an in silico and laboratory study

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Abstract

Peptide-based therapeutics have been gaining attention due to their ability to actively target tumor cells. Additionally, several varieties of nucleotide derivatives have been developed to reduce cell proliferation and induce apoptosis of tumor cells. In this work, we have developed novel peptide conjugates with newly designed purine analogs and pyrimidine derivatives and explored the binding interactions with the kinase domain of wild-type EGFR and its mutant EGFR [L858R/ T790M] which are known to be over-expressed in tumor cells. The peptides explored included WNWKV (derived from sea cucumber) and LARFFS, which in previous work was predicted to bind to Domain I of EGFR. Computational studies conducted to explore binding interactions include molecular docking studies, molecular dynamics simulations and MMGBSA to investigate the binding abilities and stability of the complexes. The results indicate that conjugation enhanced binding capabilities, particularly for the WNWKV conjugates. MMGBSA analysis revealed nearly twofold higher binding toward the T790M/L858R double mutant receptor. Several conjugates were shown to have strong and stable binding with both wild-type and mutant EGFR. As a proof of concept, we synthesized pyrimidine conjugates with both peptides and determined the KD values using SPR analysis. The results corroborated with the computational analyses. Additionally, cell viability and apoptosis studies with lung cancer cells expressing the wild-type and double mutant proteins revealed that the WNWKV conjugate showed greater potency than the LARFFS conjugate, while LARFFS peptide alone showed poor binding to the kinase domain. Thus, we have designed peptide conjugates that show potential for further laboratory studies for developing therapeutics for targeting the EGFR receptor and its mutant T790M/L858R.

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Acknowledgements

HH, BG, MM, and MB thank the Henry Luce foundation for the Clare Boothe Luce Scholarship program for financial support of this work. The authors thank Ms. Chau Anh Phan for her help with running some of the surface plasmon resonance experiments. IB thanks the Fordham University Research Office for their support. The authors acknowledge the Advanced Research Computing, Education Technologies and Research Computing department at Fordham University, a division of the Office of Information Technology for providing their assistance and access to research computing resources that have contributed to the results reported here.

Funding

This study was funded by Fordham University Research office. IB thanks NSF-MRI grant # 2117625 for the acquisition of the Fluorescence-Activated Cell Sorter instrument.

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  1. Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA

    Hannah L. Hunt, Beatriz G. Goncalves, Mary A. Biggs, Mia I. Rico, Molly E. Murray, Charlotta G. Lebedenko & Ipsita A. Banerjee

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Contributions

HLH: contributed toward in silico modeling, interpretation of data, data curation (both laboratory studies and in silico studies), and writing the first draft of the manuscript. BGG: contributed toward in vitro studies, data analysis, and writing parts of the manuscript; MAB: contributed toward data curation, in silico modeling, and in vitro studies; MIR: contributed toward data curation (cell viability studies); MEM: contributed toward data curation (SPRs); CGL: performed some of the molecular dynamics studies; IAB: contributed toward conceptualization, supervision, data analysis, editing, and writing the final version of the manuscript.

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Correspondence to Ipsita A. Banerjee.

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Hunt, H.L., Goncalves, B.G., Biggs, M.A. et al. Design and investigation of interactions of novel peptide conjugates of purine and pyrimidine derivatives with EGFR and its mutant T790M/L858R: an in silico and laboratory study. Mol Divers (2024). https://doi.org/10.1007/s11030-023-10772-x

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