Michael Gilman has an interesting article up at LinkedIn about trying to get past the current small-molecule limits of medicinal chemistry. His suggestion is “Why not RNA?”
This is not entirely crazy. Many approved antibiotics act by binding to ribosomal RNA. And Novartis’s fascinating splice-corrector LMI070, which is in clinical trials for spinal muscular atrophy, appears to act by binding specifically to the errant splice site in SMN2 pre-mRNA and stabilizing its interaction with the U1 snRNP. LMI070 is a pleasingly conventional small molecule that a non-chemist like me would not be blamed for confusing with a kinase inhibitor. Importantly, it is orally bioavailable and penetrates the blood-brain barrier. It’s proven safe enough to enter clinical development, suggesting it’s unlikely to be a pleiotropic RNA binder. Consider, too, ribocil, a very ordinary-looking molecule that Merck identified in a phenotypic screen in E. coli. It turns out to act by binding to a riboswitch, a ligand-regulated RNA structure found in the 5’-untranslated regions of certain bacterial mRNAs.
He’s got a point. I know that there have been some screens run out there, but these examples hint that there may be a lot more to be found. The promise of RNA interference and other approaches that use modified oligonucleotides has taken up a lot of the effort in this area, but small molecules probably deserve more of a shake than they’ve gotten.
I’ve had similar thoughts, though, about some other classes of biomolecules over the years. Complex carbohydrates would be another pick in the “almost completely underexploited” section, but that’s partly because the biology is such a tangle. In fact, I’d nominate them for underexploitation across the board, because polysaccharides are a lot more important than you’d think, compared to their profile in the literature (outside of perhaps immunology). That goes for cell surfaces and individual protein modification, and it goes for small molecule natural products as well. Think of the many that have odd little modified sugars hanging off them – they’re necessary for activity, in most cases, but they don’t get much respect, thus the syntheses of “Whatevermycin aglycon”. I’m not sure if I’ve ever seen a small molecule that recognizes some carbohydrate motif, and that’s probably because you almost never see anyone screening for one. Here’s a paper on the idea, and here’s a challenge from Novo Nordisk (which they have since withdrawn) to find a small-molecule glucose binder.
Lipids have come up in the context around here, too, and are starting to get more attention. There are deficiencies on the biology side here, too – if all the controversy about human dietary recommendations over the years teaches us anything, it’s that our knowledge of lipidology is completely inadequate. I got that impression when I dug into it about fifteen years ago, and nothing I’ve seen since then has changed my mind. Our biochemistry is capable of distinguishing very subtle differences in some very long and greasy molecules, and we really don’t know what’s going on yet. There are lipid-handling enzyme targets out there that have been addressed, but I’ve yet to see a pure lipid-interaction target (or screen), as far as I know. The chemical matter coming out of something like that would likely be challenging to work with, but I’d like to see some.