Silanediols are novel transition-state analog protease inhibitors pioneered in the Principal Investigator's laboratory. These structures are effective inhibitors of metalloprotease enzymes at low nanomolar (nM) levels and can cross cell membranes at rates comparable to non-silane (commercial) pharmaceuticals. B. anthracis LF is a metalloprotease and the source of anthrax toxicity. No effective inhibitor of this enzyme has been described. The initial phase of this research will produce a silanediol inhibitor of LF using known substrate specificities. The second phase will structurally alter this inhibitor to remove the peptide character and thereby improve pharmacokinetic properties. Structural fine-tuning will then yield a clinical candidate for victims of systemic anthrax infection who cannot be saved by antibiotics. -Pro-VaI-Leu-Pro-Ala-Leu-Thr- LF substrate Phase 2 and site of cleavage
