| Autor: |
Woehl, Jordan L., Kitamura, Seiya, Dillon, Nicholas, Han, Zhen, Edgar, Landon J., Nizet, Victor, Wolan, Dennis W. |
| Zdroj: |
ACS Chemical Biology; August 2020, Vol. 15 Issue: 8 p2060-2069, 10p |
| Abstrakt: |
Members of the CA class of cysteine proteases have multifaceted roles in physiology and virulence for many bacteria. Streptococcal pyrogenic exotoxin B (SpeB) is secreted by Streptococcus pyogenesand implicated in the pathogenesis of the bacterium through degradation of key human immune effector proteins. Here, we developed and characterized a clickable inhibitor, 2S-alkyne, based on X-ray crystallographic analysis and structure–activity relationships. Our SpeB probe showed irreversible enzyme inhibition in biochemical assays and labeled endogenous SpeB in cultured S. pyogenessupernatants. Importantly, application of 2S-alkynedecreased S. pyogenessurvival in the presence of human neutrophils and supports the role of SpeB-mediated proteolysis as a mechanism to limit complement-mediated host defense. We posit that our SpeB inhibitor will be a useful chemical tool to regulate, label, and quantitate secreted cysteine proteases with SpeB-like activity in complex biological samples and a lead candidate for new therapeutics designed to sensitize S. pyogenesto host immune clearance. |
| Databáze: |
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