Back at it again with another funky way to make funky peptides, gotta admit I have a type. The authors didn't provide a scheme but I whipped one up anyways :)
This time the approach is to forgo the traditional cyclisation methods (chemical ligation or disulphide bridging) and instead cyclise the peptide via a click reaction. So, what is a click reaction and why bother? Well click chemistry is the nickname given to a series of biorthogonal (meaning it doesn’t interfere with biological systems) azide-alkyne coupling reactions developed by Bertozzi, Meldal and Sharpless, its kinda a big deal and those folks won the 2022 Nobel prize for their work. There are a few reasons it would be useful to cyclise a peptide with click chemistry, a) its an orthogonal reaction which means that previously inaccessible functional groups could be included in cyclic peptides, b) a lot of ink has been spilled optimising, developing and expanding click chemistry so there’s a massive array of options and flexibility for future development, c) the click reaction produces a far more stable product that disulphide bridging and d) its not confined to the N/C terminus like chemical ligation usually is.
So with the background out of the way, what did these folks actually do? Well the paper is describes a protocol for creating cyclic peptide probes; i.e. a cyclic peptide that will bind to a target and is functionalised with a reactive handle so it can be visualised via a fluorophore. The paper is detailing a quite specific protocol, and what I think likely happened is that these folks were trying to create probes for their other research, but they realised the method they came up with was so effective that they should really publish it as a protocol (this would not be unusual).
But anyways, onto the chemistry. To create cyclic probes the researchers incorporated 2 orthogonal click reactivities into the linear sequence, a thiol-ene reaction to generate the cycle and a classical azide-alkyne for the probe functionality. The scheme does all the talking really (and was a bitch to draw) but nonetheless I think that it’s a neat demonstration of the expanding tools available for synthesising tricky peptides and versatility of click chemistry.
LeValley PJ , Ovadia EM , Bresette CA , Sawicki LA , Maverakis E , Bai S , Kloxin AM . Design of functionalized cyclic peptides through orthogonal click reactions for cell culture and targeting applications. Chem Commun (Camb). 2018 Jun 19;54(50):6923-6926. doi: 10.1039/c8cc03218a. PMID: 29863200; PMCID: PMC7433322.
