Structural biology of protease inhibitors
This research project entails a general approach to the inhibition of cysteine proteases.
Many therapeutics based on protease inhibitors are currently in late clinical trials, or are already available as drugs. However, inhibitors of the cysteine protease family are very much under represented, primarily because of flaws in their design: existing inhibitors are conformationally flexible and biologically unstable structures.
We have recently computationally designed and prepared (using ring closing metathesis) potent cyclic inhibitors of cysteine proteases that overcome these basic problems. The constituent cycle constrains the inhibitor into a beta-strand geometry that is known to favour binding to the enzyme, resulting in improved biostability, an entropic advantage to inhibitor binding, and increased potency.
This project will involve the co-crystallisation and structure determination of one or more enzyme-inhibitor complexes.