In scanning the “Metathesis in Action” section of All Things Metathesis, one will come across a number of posts that discuss the use of ring-closing metathesis (RCM) for the construction of a variety of small molecule targets that are of interest in the pharmaceutical industry. Another area within the pharmaceutical sciences that has yet to be discussed here is the use of RCM to generate stapled-peptide drugs. The idea is relatively straightforward in that a peptide containing strategically positioned olefin functionalized non-natural amino acid side chains undergoes RCM, effectively locking the peptide into a stable α-helix. This α-helical stabilization offers protection from proteases that would otherwise degrade the peptide. Also, locking the peptide in an α-helix allows penetration into cells and provides greater affinity to large protein surfaces.
A number of different approaches have been employed to covalently stabilize α-helical peptides, but in 1998 Blackwell and Grubbs were the first to employ Ru-catalyzed RCM as a means to this end.1 They employed a heptapeptide containing O-allyl ethers at specific sites which were effectively ring-closed using 20 mol % of the first generation Grubbs catalyst.
The report by Grubbs spurred further research in this area, with Prof. Gregory Verdine’s research group at Harvard University leading the charge. In 2000, they reported their results of an all-hydrocarbon stapling strategy where they examined various positions of attachment within the peptide, as well as, different stereochemistry and lengths of the cross-linker.2 These variables were shown to affect the efficiency of the RCM reaction, with no product formation in some cases and quantitative yields in others. Likewise, it was found that significant helical stabilization occurs in some examples, whereas in others the α-helix is actually destabilized compared to the experimental control.
The successes from the Verdine laboratory resulted in the founding of Aileron Therapeutics in 2005, a start-up company working to develop stapled-peptide drugs for currently “undruggable” cellular targets that can be applied to any number of human diseases. The exciting potential of technology was highlighted by a C&EN News cover story back in June of 2008.3 For additional information detailing this interesting technology, visit Aileron Therapeutics’ website.
1 Blackwell, H. E.; Grubbs, R. H. “Highly Efficient Synthesis of Covalently Cross-Linked Peptide Helices by Ring-Closing Metathesis.” Angew. Chem. Int. Ed. 1998, 37, 3281-3284.
2 Schafmeister, C. E.; Po, J.; Verdine, G. L. “An All-Hydrocarbon Cross-Linking System for Enhancing the Helicity and Metabolic Stability of Peptides.” J. Am. Chem. Soc. 2000, 122, 5891-5892.
3 Drahl, C. “Harnessing Helices: Chemical braces hold peptides in place, heralding a potential new class of therapeutics.” Chemical & Engineering News, 2008, 86, No. 22, 18-23.