There’s a fine article at C&E News on Gilead’s capsid inhibitor for HIV. For those not into virology, the capsid is the protein coat that viruses have – it’s their armor, more or less, and disrupting its formation should be a large problem for them. But finding compounds that accomplish that is a large problem for drug discovery, as the article shows. The protein latticework has to fit together beautifully to protect the virus’ cargo, but at the same time it needs to disassemble easily once the infectious attack has begun, so the hope has been that there might be some delicate balancing going on that could be tipped over with the right molecule.
Pfizer published just such molecules several years ago, in a program that had gotten underway from a phenotypic screen. Their molecule, an indole derivative, turned out (no doubt to their surprise) to fit into a gap in the HIV capsid arrangement that had been identified in the 2009 X-ray structure of the capsid proteins. That region is actually where the virus targets a particular human cell protein, CPSF6, that helps it home in on active parts of the genome, increasing its infectious success. The Pfizer molecule didn’t destabilize the capsid armor, as you might imagine, but rather stabilized it and kept it from opening up as readily, which serves to interrupt things just as well. (Pfizer had also discovered some of those capsid-destabilizing molecules as well).
The Gilead team had been working on capsid-targeting compounds for several years themselves at that point, but without a lot of success. High-throughput screening didn’t give any useful leads, so (as the article shows) the Pfizer publications really gave them something to work with. Shown at right (graphic courtesy of C&E News) is an advanced tool compound that the company has revealed. The Pfizerish core, from what I can see, is at upper left – the indole has turned into that tetrafluoropyrazole derivative, and the acetic acid amide chain coming off it, along with the branch to two aryl groups, is also in Pfizer’s original compound series, albeit in rather different form. But as you can see, the compound has grown off in other directions as well, on its way to picomolar (!) potency and greatly enhanced metabolic stability. (It had better have the latter, since it has approximately as many fluorines on its surface as a nonstick frying pan).
There are a lot of things to raise eyebrows about that compound, and I have to note that it’s not quite the one that’s in the clinic. But you’d have to assume the clinical compound is a similar beast that’s similarly beastly. So we have eight fluorines, <s>two</s> one sulfone (and one sulfonamide), an acetylene, a chiral fused cyclopropane. . .no, this is clearly, as the article says, the product of several thousand compounds worth of analoging. Is it soluble? Well, no, of course it isn’t. And there lies another point of interest.
As Jarvis’ article notes, the HIV treatment field has moved on a great deal over the years, to the great benefit of patients. New mechanism or not, there’s just not as much room as there used to be for an injectable therapy, not when most patients are well-served by an oral pill regime. But it turns out that once you actually administer Gilead’s compound, it remains active for many weeks. That’s led to the idea of some sort of subcutaneous dose that would be once a month, once a quarter – the formulations work is apparently still going on, and those now have an advantage compared to taking X pills per day on a pretty rigorous schedule.
If it hadn’t been for that, you’d have to imagine that this project would have labored long, hard, and with great skill and determination to produce something that was completely outmoded by the time it was delivered. A question that we may not get answered for a while is when the changeover occurred inside Gilead’s team, from “We’re going to target the viral capsid!” to “We’re going to come up with a long-acting HIV therapy!”. Winston Tse, the Gilead chemist quoted, says that they were never thinking about the latter, actually. (And even that field has competition of its own – read the article for more details).
There’s a lot to think about here. First, I like the fact that a molecule this large and hairy (or something similar!) is actually moving into the clinic. Yesterday’s post about all kinds of odd chemical matter could also include these things – classic organic chemistry product, just larger and more complicated (Abbott’s BCL compound Venclexta, venetoclax, is another example). Development of such molecules is definitely more challenging, but for some targets, nothing smaller may ever do the trick. Second, this is really a story of persistence and (I’m sure) of a project surviving a number of attempts to kill it. I doubt if even the Gilead scientists could furnish an accurate count of the number of near-extinction events the project survived over twelve years; you know there had to have been several. (Keep in mind, though, that just keeping a project going for a dozen years is not the recipe for it to succeed – there are many less-celebrated examples out there that can prove that!)
That brings up the third point, the one I mentioned above: this is apparently also the story of a project that might have turned into a vast waste of resources, even had it succeeded. Twelve years is a long time. There’s an old A. E. van Vogt science fiction story (“Far Centaurus“) where a crew of explorers set out on a 500-year trip, made mostly in suspended animation, for Alpha Centaurus. They arrive to find the whole system has been long populated by Earth colonists after a faster-than-light drive was discovered. That’s a real risk, on the time scale of drug development. Your competition, your patients, your pricing structure – all those things might be different by the time you arrive.
(If you look up that story, prepare yourself for a real 1940s SF experience. van Vogt was, objectively, not that great a writer, but in his prime he produced weirdly vivid tales that have an episodic, dreamlike quality to them that seems to have been driven by his rule of throwing some huge plot twist in every few hundred words, no matter what. I first read “Far Centaurus” when I was about eight, in an old paperback Groff Conklin anthology, and I haven’t re-read it in decades – but I can still quote lines from it.)