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July 20, 2011
Will Macrocycles Get It Done?
Here's an article from Xconomy on Ensemble Therapeutics, a company that spun off from work in David Liu's lab at Harvard. Their focus these days is on a huge library of macrocyclic compounds (prepared by using DNA tags to bring the reactants together, which is a topic for a whole different post). They're screening against several targets, and with several partners. Why macrocycles?
Well, there's been a persistent belief, with some evidence behind it, that medium- and large-ring compounds are somehow different. Cyclic peptides certainly can be distinguished from their linear counterparts - some of that can be explained by their being unnatural (and poor) substrates for some of the proteases that would normally clear them out, but there can be differences in distribution and cell penetration as well. The great majority of non-peptidic macrocycles that have been studied in biological systems are natural products - plenty of classic antibiotics and the like are large rings. I worked on one for my PhD, although I never quite closed the ring on the sucker.
You can look that that natural product distribution in two ways: one view might be that we have an exaggerated idea of the hit rate of macrocycles, because we've been looking at a bunch of evolutionarily optimized compounds. But the other argument is that macrocycles aren't all that easy to make, therefore evolutionary pressures must have led to so many of them for some good reasons, and we should try to take advantage of the evidence that's in front of us.
What's for sure is that macrocyclic compounds are under-represented in drug industry screening collections, so there's an argument to be made just on that basis. (You do see them once in a while). And the chemical space that they cover is probably not something that other compounds can easily pick up. Large rings are a bit peculiar - they have some conformational flexibility, in most cases, but only within a limited range. So if you're broadly in the right space for hitting a drug target, you probably won't pay as big an entropic penalty when a macrocycle binds. It already had its wings clipped to start with. And as mentioned above, there's evidence that these compounds can do a better job of crossing membranes than you'd guess from their size and functionality. One hope is that these properties will allow molecular weight ranges to be safely pushed up a bit, allowing a better chance for hitting nontraditional targets such as protein-protein interactions.
All this has led to a revival of med-chem interest in the field, so Ensemble is selling their wares at just the right time. One reason that there haven't been so many macrocycles in the screening decks is that they haven't been all that easy to make. But besides Liu's DNA templating, some other interesting synthetic methods have been coming along - the Nobel-worthy olefin metathesis reaction has been recognized for some time as a good entry into the area, and Keith James out at Scripps has been publishing on macrocyclic triazoles via the copper-catalyzed click reaction. Here's a recent review in J. Med. Chem., and here's another. It's going to be interesting to see how this all works out - and it's also a safe bet that this won't be the only neglected and tricky area that we're going to find ourselves paying more attention to. . .
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