- In today’s “Well, I’ll be darned” category is this paper, which described a way to get drug delivery into the brain that I never would have imagined. The authors are using a “calvarial” mechanism, and I’m certainly in a forgiving mood if you’ve never heard that word before, because I certainly hadn’t. The calvaria, as it turns out, is the top of the skull, and the skull bones have a lot of anatomical detail in them. The inner and outer […]
- Now here’s something that I wouldn’t have guessed. As the world knows, lipid nanoparticles have been the key to getting mRNA vaccines to work, and they are useful for all other attempts to deliver RNA cargoes into cells and probably much besides. A huge amount of effort, time, and money has been put into trying to optimize them for these purposes – all sorts of different lipids and lipid mixes, close attention to size, morphology, and cargo loading, you name […]
- The development of chimeric antigen receptor T-cell (CAR-T) therapy continues, and some really interesting new directions are being explored. As it stands, this treatment can be extraordinarily effective in some patients, and these are generally people who have been through every other option for their cancer therapy. But there are some real limitations, even for treating patients with the leukemia/myeloma type cancers that (so far) this mode is best suited for. An obvious one is the sheer amount of time […]
- Here’s a look at one of the most famous opioid agonists in the world, fentanyl. You might think that by this point we would have a pretty thorough understanding of the drug’s behavior and the factors that lead to its (notorious) potency, but such GPCR ligands it seems that there’s always more to discover. The authors here are working off recent results from patch-clamp receptor assays in whole cells that suggested that fentanyl (but not the classic opioid ligand morphine) […]
- Time to think like a biochemist! And that means paying close attention to energy transactions in a cell, because the science of thermodynamics makes it very, very clear there there is always a bill that has to be paid. Most of the time, the currency involved is of course ATP, since breaking that down to ADP gives you an immediate payout. ATP hydrolysis and the other sources of chemical energy (like acetyl-CoA) function as “battery packs” for all sorts of […]
- Here’s a paper evaluating a popular AI/ML model for cofolding ligands and proteins, Boltz-2. This is of course a problem of extreme interest to the drug discovery community, as well as to all sorts of people working on cell biology, structural biology, and related fields. It’s been one of the goals for decades to start from scratch with a protein sequence and a small molecule and be able to say “Does this molecule bind to this protein? How well?” And […]
- Here’s the other cognition/aging/Alzheimer’s paper that caught my eye. In a similar way to the work I highlighted yesterday on proteins released by the liver affecting the blood-brain barrier and overall brain function, this one is finding another external signal, from from an unexpected direction. The authors studied the intestinal microbiomes of mice as they aged, and found that species that produce medium-chain fatty acids become more and more prevalent. Then a complex series of events start taking place: these […]
- I’d like to highlight a couple of interesting papers with a bearing on Alzheimer’s and aging in general – well, I hope that they will turn out to have one, because right up front I have to note that they’re both in rodent models. But the unusual mechanisms in both cases are the sort of thing that could translate to humans, and could also be fairly readily checked. We’ll do one today and another tomorrow. This paper is building on […]
- I really got a kick out of this recent paper, but that’s probably because I’ve always enjoyed the whole “templated ligation” or “kinetic target-guided synthesis” field. There are several ways to describe it in the literature, which doesn’t make searching for papers any easier, but the basic idea is that you get two partner species to react in the presence of a binding site or surface. If you pick your chemistry right, that reaction/ligation/bond formation/condensation is something that normally has […]
- Let’s start off the week with some good news. There was a small company called Anacor that specialized in boron-containing drug leads, especially for infectious diseases. They had some shots at the clinic in that area and had an antifungal (tavaborole) approved by the FDA, but their biggest success was a topical medication for dermatitis called crisaborole. That’s a PDE4 inhibitor, although it has to be said that the exact mechanism for its efficacy in this disease is (to my […]
- We find ourselves in a situation where chemistry is intruding on current events, and I’m referring to something that not everyone seems to have thought about: fertilizer, and especially nitrogen fertilizer. What it is, how it’s used, and especially where it comes from. Intro to Fertilizer Now that's a grabber of a subhead, right? But if you’ve bought a bag of the stuff for your garden or your houseplants, you’ve seen the three numbers used to show the strength and […]
- I enjoyed this paper, because it plays to my own prejudices. I’ve long believed that assays and experiments should be conducted as close to the real biological systems as is feasible, and that if you are (perforce) starting in more simplified ones, that you should move up the scale as soon as you can. That means if you show up with purified protein assay data, I’ll ask when it’s going into cells, and if you have cell data I’ll ask […]
- Let’s have a look at the unique situation of UniQure. It’s a story about central nervous system disease therapy, that’s for sure. And it’s a story about clinical trial design, and it’s also a story about new and challenging modes of treatment working their way into such human trails. But unfortunately, it has turned most of all into a story about regulatory affairs as they are run under the Trump administration. This is all about a potential therapy for Huntington’s […]
- Here’s a really interesting (but rather unnerving) look at the state of “big data” in biomedical science. The author had been working on some software tools to find copy-pasted blocks of data in large data sets as a method of fraud detection. Such duplications have been the subject of controversy in papers from the SĂĽdhof lab at Stanford (and you can get two different sorts of perspective on that case with those links) and also with the Pruitt lab at […]
- I’ve written a number of posts here about weird natural products (and another such roundup is in the works), but I couldn’t resist highlighting this paper. The compounds discussed (which have been found to be produced in bacteria, specifically one human-pathogenic species, Nocardia ninae) are not huge and bewilderingly complex. Natural products have plenty of those kinds of structures, but these are very small molecules indeed. They’re just really unlikely ones. That’s because they’re diazo compounds – yep, like good […]
- Quick preface: For those who have asked, my in-laws in Iran are (so far) all OK, but we are all of course in an extremely dangerous, stupid, and random situation right now. So yes, it does feel a bit odd to be writing about science and medical topics when there are so many other things going on (and going off) in the world. But this is one way I keep my own equilibrium, and I hope that that word of […]
- Here’s a transcript of a recent podcast over at Nature in their Careers section. They’ve been doing a series on what they feel are taboo topics in the workplace, and previous ones have covered things as disparate as alcohol abuse and religious convictions. This latest one, though hits on a subject that might not sound, to someone who hasn’t been in academia, like that much of a divisive issue. But it is: leaving academia to go into industry. The host […]
- Here’s a real oddity for you in the field of antiviral mechanisms. Over the years people have looked at all sorts of viral infection and propagation mechanisms, trying to find vulnerabilities to exploit. But “cell membrane stiffening” leading to decreased fluidity and impaired viral entry has never, to my knowledge, been one of them. So how to you get that toughened-up membrane state? The authors say that this is downstream of the mechanosensor Piezo1. That’s an interesting system – the […]
- One of the things that seems clear (after many years of writing this blog and fielding questions about drug research from all and sundry) is that most people outside the field don’t realize the failure rates for drug trials. And they don’t realize how often it is that seemingly good ideas just don’t pan out. The recurring proposals to de-emphasize confirmatory trials for efficacy in favor of moving ahead with getting medications to patients is an example of this. Advocates […]
- This perspective is well worth reading, even if you find yourself arguing with some parts of it (here's a freely available preprint version). Longtime drug discovery guy Mark Murcko titled it “The Affinity Advantage”, and I think this gets across the point he’s trying to make: “I argue that a greater emphasis on optimizing binding affinity will accelerate drug discovery. Note that “optimizing” is not always synonymous with “maximizing” So let’s talk about that! As the paper notes in the […]
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