PCSK9 is a drug target that’s famous in several directions. If you’re interesting in human genetics, it’s famous as an example of a “human knockout” – people with nonfunctional PCSK9, and there are a handful, have extraordinarily low levels of LDL, a finding that immediately got drug companies interested in finding inhibitors. If you’re interested in the business side of the industry, then PCSK9 is famous because there are competing antibodies from Amgen and Regeneron/Sanofi fighting it out in the market, with a Pfizer one coming along shortly. Similarly, if you’re into regulatory issues and outcomes, this is a big area as well. LDL lowering is something that these therapies certainly can deliver – but does that translate into real-world endpoints in mortality and morbidity? Since the progress of cardiovascular disease is slow, no one’s quite sure yet. Both players in the field are gathering data, in the hopes that their products will see much wider use once their impact on patient outcomes clears up – it’s safe to say that uptake of both drugs has been slower than some people had hoped, for just this reason.
Now we’re back to another biochemical reason to find this target interesting. A joint paper from a team at Pfizer and one at Berkeley (the Cate group) is out on an interesting and unusual mechanism. They report a small molecule, PF-06446846, inhibits PCSK9 expression by directly acting on the ribosome, stalling it at a particular codon as the protein is being assembled. Ribosome stalling is a topic that’s been around for many years – there are several antibiotics (like erthythromycin) that use it as their mechanism of action (it can also be part of normal gene regulation in some bacteria). The molecule itself (at right) is not particularly small (molecular weight of 433), but it’s certainly not a gigantic weirdo thing, either. There’s nothing about it that would make you think “Yeah, that’s going to do something unexpected”; it’s an assembly of perfectly reasonable med-chem pieces. You never know!
This series of compounds was discovered by phenotypic screening, and I’ll bet that the mechanism came as a surprise. It certainly surprised me – you wouldn’t think that monkey-wrenching the ribosome would be (or even could be) a very specific process, which is surely why it shows up in the kill-or-be-killed world of antibiotics. A number of control experiments ruled out general effects on protein synthesis, though, or mechanisms targeting messenger RNA. Instead, it looked as if the drug’s effect depended on the specific amino acid sequence of PCSK9 itself, which suggests something to do with the ribosome’s “tunnel” region, which the protein chain moves through during the synthesis process.
There are peptides known that do similar things, but (to the best of my knowledge) this is the first small molecule that does it in such a protein-specific manner. The details of the mechanism are still fuzzy, because although there are a few other proteins whose expression is also altered, they don’t have much in the way of common features – you can’t just predict by the primary sequence what’s going to be affected. There’s something subtle going on in the ribosomal exit tunnel that’s going to require a lot of work to figure out.
But that work could well be worthwhile. Being able to do this specifically, and to order, would be a major advance. There’s no guarantee that such a broad application of this concept is possible – in fact, there are many reasons to think that it might well not be – but this example alone is more than most people would have thought likely. Affecting transcription and translation through small molecules is a tricky business, and there have been a lot of failures in the area over the years. The biology is ridiculously complex, when viewed through a small-molecule lens, and a lot of drug discovery efforts have disappeared into those swamps. Is this a patch of dry ground, or not?