I’m really glad to see this Perspective article in the Journal of Medicinal Chemistry, not least because it hits on a theme that I emphasize whenever I get a chance to speak to graduate student chemistry audiences. The author, Bart Roman, is pointing out that (1) biologics are relentlessly expanding their role in the landscape of approved drugs and (2) this means that organic and medicinal chemists have a new area to work in.
Not all of them have thought that way over the years, for sure. Many of these biologic agents (monoclonal antibodies, to pick a big class of them) are aimed at targets that are very difficult to affect with traditional small molecules. The natural tendency has been to leave the antibody folks to it and assume that this area is outside the purview of synthetic organic chemistry. After all, antibodies aren’t discovered or produced by traditional chemical technologies, and they have rather different behavior once dosed in animal models or patients. And they’re usually developed by completely different parts of an organization, assuming that the company even does small-molecule drug discovery and antibodies at the same time.
But as Roman says, “Small molecules are no longer the rule, and biologics (are) no longer the exception“. Medicinal chemists shouldn’t step aside for biologics or try to pretend that they aren’t there. Instead, we should be trying to claim some of this territory as our own, using the specific skills that we can bring to the process. This could have the desired effects of making both biologic drugs and medicinal chemists simultaneously more valuable.
The article specifically mentions working on late-stage protein modification techniques and post-translational modifications in general, and that seems like a sound plan. Modifying the plain amino acid sequence of a given protein is most easily done through molecular biology, but adding non-amino-acid tags are another thing entirely. It becomes harder and harder to use biological methods for those as they get more exotic (non-natural amino acids, genetic code expansions, and so on), which provides a real opportunity for chemical synthesis to step in. More and more of this sort of work has appeared in recent years, and there are a lot of opportunities yet to be realized. In the same way that late-stage functionalization of “regular” synthetic molecules or natural products has been increasingly employed, being able to modify proteins after they’re already made is a goal worth reaching for.
What does that get you? An obvious application is making tools for chemical biology (fluorescent tags and other markers), but you can also make real therapeutics. Antibody-drug conjugates, for example, have been around for quite a while now, but they seem to be undergoing an upsurge. The hot field of bifunctional molecules (targeted protein degradation is just the beginning) also can surely expand into protein-small molecule hybrids. There are clearly a lot of things yet to be discovered in these area, and we’re going to need better and easier ways to make protein-small molecule conjugates in order to explore that huge space.
Freeman Dyson famously argued that scientific fields go through periods were they’re driven forward by new ideas and through periods when they’re driven by the availability of new tools that allow experiment that couldn’t be performed before. The merger of synthetic organic chemistry and molecular biology is ready, I’d say, for the latter. If every new modified protein is a whole project in itself, a lot of experiments just don’t get tried, and we don’t learn as much. But if there are a variety of reasonably good ways to make such things, we can explore all sorts of hypotheses as they come up, or just turn out libraries of them and see what happens.
The larger point is that medicinal chemists need to avoid the temptation to bemoan their fate as the world changes around them. Instead, we should be looking for new territories to explore, new places to make our own. Synthetic organic chemistry (to put it mildly) is not a widely distributed skill set – nobody else is going to do these things, or certainly not as well as the organic chemists can. So let’s show how valuable it is!