Chemical biology of matrix metalloproteases

Matrix Metalloproteases (MMP) inhibition is currently brought to the focus of medicinal chemistry research due to their essential roles in many human diseases. To elucidate the functions of each individual MMP, it is imperative to synthesise small molecule/probes which can selectively target a particular MMP instead of those which exhibit broad spectrum inhibition against the whole family. In this project, we aim at profiling MMPs substrate specificities in a high-throughput manner using small molecule microarrays as well as elucidating their biological functions through activity-based protein labeling. Herein we introduce synthetic routes toward different P1a?? substituted MMPI warheads and their use in the MMPI library synthesis on solid phase. In addition, by taking the advantages of the relative ease and convenience of a??Click Chemistrya?? in constructing focused chemical libraries, we have been able to apply this strategy to synthesise a 96-membered library of metalloprotease inhibitors followed by in situ screening. Moreover by using the same strategy, we successfully demonstrate that the facile synthesis of various affinity-based hydroxamate probes that enables the generation of activity-based fingerprints of a variety of metalloproteases, including matrix metalloproteases (MMPs), in proteomics experiments.

Author dc:creator

• WANG JUN

• Matrix Metalloprotease, activity based probe, click chemistry, small molecule microarray, high-throughput screening