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Category → What is Chemical Biology?

What is Chemical Biology? Perhaps it’s Peptidomimetics

Disclaimer: I am not an expert. In fact, this series of blog posts is as informative  to me as it is to you. Probabl

y 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!

This doesn't seem like Chemical Biology to me...

No, not THAT kind of mimicry! (Credit to Flickr user christopherasmith58102)

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:

  1. 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.
  2. 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.
  3. 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.
A peptido-mimeticist's dream come true

Beta-Peptides and Peptoids have structures that make that protease resistant

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.

Credit to the University of Maine MechE website

Gramicidin is a cyclic peptide that forms pores in bacterial cell membranes

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!

What is Chemical Biology? No… seriously.

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!

NOT Chemical Biology

Maybe one day, research like this could be chemical biology

The next several months are pretty big for me.  Soon, I’ll be taking the GRE and deciding where to go for my PhD, but I honestly have no idea where I want to study.  Because of my current research and classes I’ve taken, I know that Chemical Biology is the field for me.  The only issue is, when asked recently by friends, family, and random strangers  what Chemical Biology really is, I’m kind of at a loss.

For me, Chemical Biology means probing biological systems with chemical agents.  Recently, I’ve had a chance to talk to a couple PhD candidates (including our very own  Christine Herman) in Chemical Biology, and they all had varied definitions.  Christine’s and my research could not be more different; she does research in bioassays, and I do a lot of work in peptidomimetics and drug discovery.  Her research is in the analytical department, and mine in the organic.  It surprised me to learn that she classified herself as a chemical biologist as well.  This led me to a couple conclusions:

Chemical Biology is less of a specific field but more of a classification encompassing a wide range of different kinds of research.  Things that would have once been considered organic chemistry (such as what I do), analytical chemistry (what Christine does), or even physical chemistry (see some later posts!) are now under the great big umbrella that is Chemical Biology.  So, what’s a young blogger to do?  Over the next several months, I’m going to examine different areas of research in Chemical Biology, one by one.  I’m planning on getting in touch with some of the leaders in field.  Hopefully, this will be fun for everyone, and help me decide where I want to do my PhD.

Next Monday tune in for a subject near and dear to my heart:  peptidomimetics!  Any suggestions on who to talk to?  Post below!