Silanediol inhibits the metalloprotease angiotensin-converting enzyme (ACE; see: Sieburth, Nittoli, Mutahi, and Guo """"""""Silanediols: A New Class of Potent Protease Inhibitors,"""""""" Angew. Chem. Int. Ed. Engl. 1998, 37, 812-814.) The proposed research will fully characterize the inhibition of ACE with silanols by first preparing the isomers in enantiomerically pure form. The resulting inhibition data will allow the silanediols to be compared to benchmark ACE inhibitors. Inhibitors of thermolysin will be prepared for comparison with analogous phosphorus-based inhibitors of thermolysin, using both kinetic data and X-ray crystallography at the enzyme active site (in collaboration with Brian Matthews). Application of silanediols to current medicinal chemistry targets will focus initially on the matrix metalloproteases (MMPs, especially collagenase) using combinatorial methods to survey the structure-activity relationships with the silanediol inhibitor core. Inhibitors of the newly identified metalloprotease, anthrax lethal factor (LF) will also utilize combinatorial chemistry to identify the requirements for substrate recognition by LF, for which very little is known.
| Juers, Douglas H; Kim, Jaeseung; Matthews, Brian W et al. (2005) Structural analysis of silanediols as transition-state-analogue inhibitors of the benchmark metalloprotease thermolysin. Biochemistry 44:16524-8 |
| Mutahi, Mwangi wa; Nittoli, Thomas; Guo, Luxuan et al. (2002) Silicon-based metalloprotease inhibitors: synthesis and evaluation of silanol and silanediol peptide analogues as inhibitors of angiotensin-converting enzyme. J Am Chem Soc 124:7363-75 |
| Chen, C A; Sieburth, S M; Glekas, A et al. (2001) Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease. Chem Biol 8:1161-6 |
