Disclaimer: I am not an expert. In fact, this series of blog posts is as informative to me as it is to you. Probably even more so. My views and the views of people interviewed for this blog do not, in fact, reflect what exactly “chemical biology” is, but only a snapshot. Please direct any comments or suggestions below!
Peptidomimetics is something I think about all the time. So, I decided it would be a pretty good starting point for this series, especially considering that right now it’s finals week and I barely have enough time to be running a synthesis, much less studying for finals. But that’s beside the point, because I’m very excited to learn more about peptidomimetics (and who needs to study for finals when you can do research instead, am I right?)!
What is peptidomimetics? From what I’ve seen, it’s pretty much exactly how it sounds. The essential goal of the field is to take a peptide of interest, which usually means that it’s bioactive or important in some way physiologically, and synthesize and test organic mimics of it to fulfill a number of different goals. So if we have bioactive peptides why not just use them as drugs? Because peptides have some inherent problems to their usage that peptidomimetics seeks to solve:
- Protease Resistance/Serum Stability: One of the main reasons that peptide drugs (mainly mimics of allosteric regulators) have been largely unsuccessful. When a peptide is taken up by the body, either intravenously or orally, the body has a suite of enzymes (such as proteases and E3-Ubiquitin Ligases) which degrade small peptides and foreign ingested proteins. While these processes are important in metabolism and immune function, we would rather our peptides not be degraded by the body. One of the main goals of peptidomimetics is to avoid the body’s natural defense against peptides and to get at biological targets.
- Membrane permeability: Most biological targets are located inside cells. In order to get your favorite peptide into a cell, you need to cover it with lipophilic groups (or else somehow reduce the charge) to help it squeegee its way (technical term) into the cell. Small molecules, being generally much smaller, rigid, and lipophilic, rarely have this problem. Because peptides routinely break Lipinski’s Rule of Five for drug-likeness, special provisions must be taken in synthesis and design.
- Conformational Restriction: Very often, peptides are considered “floppy.” They require an optimal “active conformation” to bind to or inhibit other enzymes. Very often, peptidomimetics seeks to modify peptides by constraining them into a more stable and active conformation, thus reducing the entropic cost of a peptide’s action.
So what kind of research do people in peptidomimetics do? This kind of research is widely diverse but can be divided into a few categories. Beta peptides are peptides which have the amine group bound to the beta carbon instead of the alpha. This allows for (a) more membrane permeability and (b) greater protease resistance. Already, beta-peptides are being researched as antimicrobials, and have been shown to readily form alpha-helices. Peptides are another kind of amino acid mimic that are widely used. Instead of having the R group on the alpha carbon, they have it on the amine group. They’re also called N-substituted glycines. Again, you see here greater protease resistance because proteases do not recognize these amino acid mimics. In addition, the lack of amide protons and achirality of the alpha carbon gives rise to greater membrane permeability. However, the pretty secondary structures you can get with beta-peptides are impossible to achieve with peptoids. You can read more about beta peptides and peptoids and their antimicrobial potential in this great review from Chemical Biology and Drug Design. For more reading, you can check out this cool review on incorporating beta-peptides and peptoids into the same chains from ChemBioChem. Imagine how much trouble that would be without solid phase peptide synthesis.
Another branch of peptidomimetics involves regular, plain-old amino acids. Very often, it is possible to restrict the conformation of a peptide to its active conformation by cyclizing it, especially if the active conformation of the peptide includes a loop or turn. This accomplishes what I was talking about earlier: paying the entropic barrier up front, and locking a peptide into a smaller series of conformational possibilities. Cyclic peptides are also more protease-resistant due to a restricted conformation, and are more membrane permeable, because of (a) the smaller size and (b) the elimination of the N and C termini, making the molecule overall more nonpolar. The European Journal of Organic Chemistry has another good review on peptidomimetics that you can check out at your leisure.
This sounds a whole lot like medicinal chemistry to me, so far. So why put it into the large umbrella that is Chemical Biology? I would argue that peptidomimetics belongs in Chemical Biology because (a) peptides are biological molecules, and bioactive molecules are the focus of Chemical Biology and (b) these peptidomimetic molecules can be modeled in vivo and in vitro and (c) the field incorporates aspects of organic chemistry, classic biochemistry, and some cell biology, and this duality of research (to me) characterizes Chemical Biology.
I hope this was as helpful to you as it was to me. I think peptidomimetics is pretty cool, and wouldn’t mind going into it in grad school. This review is really small in scope and I encourage you to read the reviews that I’ve linked to. What would you like to see next Monday? Right now I’m thinking about Native Chemical Ligation, but I could be persuaded otherwise. Feel free to post in the comments below!
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