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March 13, 2013
Getting Down to Protein-Protein Compounds
Late last year I wrote about a paper that suggested that some "stapled peptides" might not work as well as advertised. I've been meaning to link to this C&E News article on the whole controversy - it's a fine overview of the area.
And that also gives me a chance to mention this review in Nature Chemistry (free full access). It's an excellent look at the entire topic of going after alpha-helix protein-protein interactions with small molecules. Articles like this really give you an appreciation for a good literature review - this information is scattered across the literature, and the authors here (from Leeds) have really done everyone interested in this topic a favor by collecting all of it and putting it into context.
As they say, you really have two choices if you're going after this sort of protein-protein interaction (well, three, if you count chucking the whole business and going to truck-driving school, but that option is not specific to this field). You can make something that's helical itself, so as to present the side chains in what you hope will be the correct orientation, or you can go after some completely different structure that just happens to arrange these groups into the right spots (but has no helical architecture itself).
Neither of these is going to lead to attractive molecules. The authors address this problem near the end of the paper, saying that we may be facing a choice here: make potent inhibitors of protein-protein interactions, or stay within Lipinski-guideline property space. Doing both at the same time just may not be possible. On the evidence so far, I think they're right. How we're going to get such things into cells, though, is a real problem (note this entry last fall on macrocyclic compounds, where the same concern naturally comes up). Since we don't seem to know much about why some compounds make it into cells and some don't, perhaps the way forward (for now) is to find a platform where as many big PPI candidates as possible can be evaluated quickly for activity (both in the relevant protein assay and then in cells). If we can't be smart enough, or not yet, maybe we can go after the problem with brute force.
With enough examples of success, we might be able to get a handle on what's happening. This means, though, that we'll have to generate a lot of complex structures quickly and in great variety, and if that's not a synthetic organic chemistry problem, I'd like to know what is. This is another example of a theme I come back to - that there are many issues in drug discovery that can only be answered by cutting-edge organic chemistry. We should be attacking these and making a case for how valuable the chemical component is, rather than letting ourselves be pigeonholed as a bunch of folks who run Suzuki couplings all day long and who might as well be outsourced to Fiji.
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