In The Pipeline

Autoimmune disease is a major problem and a major puzzle. I've written about various aspects of this over the years, covering a wide range of diseases. And you're going to have to cover a wide range, because the list of human diseases that are clearly driven by autoimmunity or have some such component is long and fearsome. Some of these start early in life (like most Type I diabetes), others gener

Cells are full of positively and negatively charged molecules, and their behavior (by themselves and with each other) is a key feature of the chemistry of life. It’s also a key feature of the behavior of drug molecules, because a strongly charged molecule often has trouble working its way through the lipid membranes that surround cells (unless it’s picked up by one of the “active transport” system

This is a news item that I wish weren't worth writing about. But unfortunately it is, for several reasons. This article here in Science details how in 2016 a decision was made about worldwide polio vaccinations that seems to have completely backfired. The background is that there are/were three types of poliovirus. Type I is still out there circulating, unfortunately, despite years (decades) of ef

I wanted to highlight this recent paper because it's a look at a subject of great interest: can RNA be used as a disease therapy, outside of its use in vaccines? Vaccination, after all, takes advantage of the built-in amplification (and built-in memory) of the immune system, whereas most other diseases are going to need larger doses of RNA constructs for a much longer time (in some cases, for the

Readers here will know that I like to cheer on work in new antibiotics and antibacterials in general (the resistance problem is as real as can be), and also that I am really encouraged about all the new therapeutic modes of action that we've been uncovering the last few years. So as you'd guess, I'm very glad to see work like this new paper, where targeted protein degradation is turned into a weap

This paper is a good overview of safe handling of a reagent that most synthetic organic chemists have used at one time or another, lithium aluminum hydride. LAH shows up all over the place as a reducing agent, and you can buy it as a dry powder, as a solution, and in solid pellets and chunks for larger-scale reactions. But for such a widely used substance, it has some significant safety hazards. I

This is not going to be a post about AI, but it has a bearing on the subject. I was recently at a conference where someone from outside the drug discovery field (but with a technology background) made a pretty extravagant statement about how biology was now being modeled in silico. My objection to that was and has always been that we don’t know enough yet to do any such thing. An easy way to

There’s been so much news about the computational advances in protein structure and design that I think that people outside the field (and news articles written for that wider audience) tend to miss out on what could be a very important application: the prediction of smaller non-natural peptide-like structures. There is a ridiculously large number of possible structures in this area, and many of t

I wrote back in February about the pileup in GLP-1 drug development, and even that post didn't get to all the things going on in this area. There's been even more news recently, so I thought that a quick update might be a good idea. Roche/Genentech jumped into this area with a $2.7 billion dollar buyout of Carmot late last year, and they already have good news about that investment. The mean weigh

It’s hard not to think that scientific publishing is under assault these days, and it's also easy to think that the publishers are not weathering it too well. The broader changes are the obvious ones that have affected all printed media for years now - when was the last time that you held a newspaper in your hand? Or even a printed copy of a scientific journal? Business models in all sorts o

I wrote not long ago about legislative efforts to try to decouple Chinese contract firms from US biopharma research. That's a fraught subject, because it brings up a lot of hard questions. Are Western firms too exposed to the uncertainties inherent in dealing with Chinese outsourcing firms, which include possible connections with the Chinese government itself and worries about the security of inte

Here's a new paper whose title asks a question that's on a lot of peoples' minds these days: "How successful are AI-discovered drugs in clinical trials?" We are (very arguably) getting to the point where this question is worth asking, and the very first part of that argument is what qualifies as an AI-discovered drug. The paper's Supplementary Material gives the details on what compounds have been

Now that I'm back (from some traveling) it looks like the first item of business is the advent of AlphaFold 3. That Nature preprint (which is open access) says that this extends the predictive powers of the software to other classes of molecules and to complexes between them. I had expressed some skepticism in the past about how easy that would be to do in the case of small synthetic molecules - y

Blogging Resumes Shortly

Over the years there have been several claims of "metal-free" versions of coupling reactions that are typically catalyzed, and it's safe to say that most (all) of these have come to grief eventually. The lesson that people are gradually learning is that it's very, very hard to ensure that your system is actually free of metals! Some of these reactions are wildly, extravagantly catalytic, and if yo

Here's one of those massive chem-bio discovery papers that will probably never stop seeming like science fiction to people like me who started in this work in the late 80s and early 90s. It's from several groups in Vienna in collaboration with Pfizer, and it's exactly what the title promises: a large-scale chemoproteomics effort, done with a fragment-sized library. The paper takes 407 structurally

There are several stands of Sanguinaria canadensis blooming right now in the back yard here. It's a native woodland flower commonly known as bloodroot, but we owe its density in our yard to the efforts of my wife, who's a member of the local garden club. Bloodroot is a very early spring flower here in the Northeast, and sends up its blooms before its leaves. They don't last all that long, so you h

We're still learning about how proteins interact with small molecules, with each other, and with the solutions that they sit in. Witness this recent paper, which quantifies an effect that has been showing up in other biophysical studies (such as NMR and single-molecule microscopy). Positively charged proteins just don't seem to diffuse around as much inside cells as you would expect them to. That

Back in 2010, Halaven (eribulin) was approved by the FDA, and I noted at the time that it was surely the most synthetically complex drug substance that had ever made it to market. Now the chemists at Eisai are back with another related compounds that is even tougher (see at right). This new paper details development of its scale-up route (more here and here), and the compound is now in the cl

News has come of the start of a new AI-centric biopharma company, Xaira. They say that have over a billion dollars in funding lined up from ARCH Venture Partners and a number of other investors, and there are a number of marquee names involved (such as David Baker and his protein-design group at Washington). Interestingly, the head of the new company is Marc Tessier-Lavigne, whose name may well re