- I definitely need to cover this recent work from Merck, because (1) itās very interesting scientifically and (2) it has over 130 authors on the paper (!) It details the industrial synthesis of enlicitide, which is a beast of a macrocyclic peptide (see below!) Just looking at the structure tells you that this must be a ferociously active molecule with huge commercial potential, because there is just no way that anyone is going to make this on scale – or […]
- I wrote here last year about the clinical trial results for the first ābifunctional degraderā molecule to make it that far, vepdegestrant from Arvinas and Pfizer. That post will send you to some background information about this class of molecule, but suffice it to say that they represent a completely new mode of action (destruction of a target protein in the living cell as opposed to chemical inhibition of it). As such, this program has been watched closely, and the […]
- I think that many synthetic organic chemists will be able to relate to the approach described in this paper, on software-aided route design. Its authors are trying to make such software take a viewpoint from higher over the synthesis, rather than working out every reaction. As noted in this commentary, for larger molecules that can leave you with a forest of rather-similar routes that differ in choice of protecting groups, relative oxidation states, order of reactions and other details that […]
- Iāve written here many times about various post-translational protein modifications. Thatās a huge field of study, because it has become more and more clear over the years that itās not so much that living cells have huge numbers of different protein sequences in them (although they have plenty!) itās that every protein seems to be modifiable by a long list of add-ons. These include (but are absolutely guaranteed not to be limited to!) phosphorylation, ubiquitination, farnesylation, glycosylation, acetylation, palmitoylation and […]
- Well, I know by now what happens when I bring up vaccines, but Iām going to do it anyway because we have a lot of news. As many will have heard, news broke recently of several large-scale studies of safety for the coronavirus and shingles vaccines. Hereās the New York Times on the story, and hereās the Guardian. These were done by evaluating millions of patient records, and seem to have concluded that these vaccines are in fact safe, with […]
- When appropriate I usually wait until the end of one of these posts to draw attention to the way that its subject dovetails (or not) with the current fashion for AI/ML techniques. For one thing, I find it helpful to remember that really new results cannot generally be obtained by asking an LLM system that is trained on piles of existing text which it has blended and chopped and extruded back to you. Thatās because those new results were not […]
- OK, letās talk helium today. A while back I wrote about the Haber-Bosch process for making ammonia (and thus making nitrogen fertilizer), and how that was already being impacted by the then fresh and new Iran war. Well here we are in the first week of May, and urea prices can best be described as āhigh and choppyā, jumping around (as does crude oil) on news of the war. Hereās the freight-on-board futures price for the Middle East, and if […]
- Dear Dr. Bhattacharya: I write to inquire about your state of mind. That may seem an unusual request, but these are unusual times, and God knows you have been appointed to serve in an extremely unusual administration. As Director of the NIH (a post – letās be frank here – that for many years Iām sure you never seriously imagined that you might hold) you have of course a great many responsibilities, facing not only your direct reports and employees, […]
- We have quite a regulatory situation developing around a drug called avacopan (Tavneos), which is given to patients with a particular type of vaculitis. Thatās a complex disease area, and comes in several varieties, but a common theme in many of them is an autoimmune attack against various proteins found in neutrophils. The drug is an antagonist of the complement 5a receptor in the innate immune system, and itās given along with other immunosuppressants. It was developed recently by a […]
- This article (open access) is the latest in a long, long series of implementations of an idea that is very simple to state and very difficult to achieve. That is, what if we (1) had a set of machines that could run organic chemistry reactions for us, ones that (2) could also analyze how well these reactions worked (yield, purity and so on), and that (3) could then use some sort of software evaluation of the data to set up […]
- Think about it: have you every heard of a case of heart cancer? Itās very rare indeed, and why thatās the case has been a longstanding puzzle. This new paper (here at Science) seems to have found a big piece of the answer, though. Cardiomyoctes are a rather special class of cell, but one of the fundamental things that make them special is that they are always in motion and under mechanical stress. If you raise them correctly in a […]
- You can put this one in the āreactions I never expected to seeā category, because itās a way to selectively functionalize aryl rings with multiple fluorines on them. And no, I donāt mean āfunctionalize at the carbon(s) that arenāt fluorinated yetā or even ākick out the most likely SnAr leaving group fluorineā. This is stepping and and replacing fluorines with H, D, alkyls or other aryls. The reason this looks so odd is that most of the time in organic […]
- We have some really interesting progress in pancreatic cancer to talk about, both on the small-molecule and the mRNA vaccine fronts. Letās do the small-molecule ones first, because those were honestly more unexpected. So to lead off, Revolution Medicines announced at the AACR meeting in San Diego that their drug daraxonrasib showed strong efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). That is a very, very difficult to treat population – these people typically have only a few months […]
- Living in New England, we tend to get out into the yards, parks, and gardens this time of year because weāve pretty much had it with winter. Of course, winter hasnāt always had it with us – weāve had frost here the last couple of mornings, so itās not exactly time to put the tomatos and cucumbers out there yet. But whenever the weather does start to warm up, so (unfortunately) does the threat of tick-borne diseases like Lyme. That […]
- Translation of mRNA into proteins is a nonstop, nonnegotiable process that is essential to the life of a cell, and it has acquired a *lot* of evolutionary tuning over the last few billion years. In critters like us with nuclei and other such organelles (the big happy club of eukaryotes, to which so many of my readers belong as G. K. Chesterton used to say), thereās a very important protein complex called elF4F. Thatās short for āeukaryotic initiation factor 4F", […]
- This is not going to come as a surprise to readers of this site, because even if you donāt agree with this contention you have certainly at least been exposed to it: the Cochrane Review folks have examined the clinical evidence for anti-amyloid antibodies as therapies for Alzheimerās and found, well. . .you know what they found: The effect of amyloidābetaātargeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild […]
- Artemisinin-based therapies are the absolute mainstay of malaria treatment the world over, so this new paper deserves attention. The drug is often given in combination with the older aminoquinoline agents like choloroquine, piperaquine, and amodiaquine, but the authors here make a strong case that this is actually counterproductive. As the paper notes, heme is central to the mechanism of action for both kinds of drugs. The aminoquinolines bind to it and affect heme homeostasis, and may well product toxic adducts […]
- I spent a day at Williams College last week, which I enjoyed very much, and I found a part of my lecture there overlapping with a big topic in undergraduate education. I have a section in several of my talks where I speak about AlphaFold-type machine learning and its implications for drug discovery, and that seemed to fit rather closely into concerns that many professors are having about the effect of AI systems on coursework and learning. Iām sure that […]
- I often get asked what areas of drug discovery look most likely to bear AI-driven advances into the clinic, and my usual answer is ātherapeutic antibodiesā. Thats because itās a protein-centric problem in the actual modeling, and we know quite a bit already about antibody structures (at least as compared to the much large wild-type protein structural landscape). And thatās because antibodies themselves are a (relatively!) constrained space within that larger one, although donāt let anyone tell you that itās […]
- If you look at cells dispassionately, one of the things that strikes is that man, do we ever have a lot of ribosomes. These are of course the protein-synthesis machines that are kept humming nonstop as RNA sequences are translated into protein sequences, and ribosomes themselves are structurally a mixture of proteins and some unusual RNA molecules all their own. The peptidyltransferase center (PTC) where the actual synthesis of new peptide bonds takes place is itself a flat-out ribozyme, an […]
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