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An Irreversible Inhibitor to Probe the Role of Streptococcus pyogenes Cysteine Protease SpeB in Evasion of Host Complement Defenses.


ABSTRACT: 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 pyogenes and 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. pyogenes supernatants. Importantly, application of 2S-alkyne decreased S. pyogenes survival 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. pyogenes to host immune clearance.

SUBMITTER: Woehl JL 

PROVIDER: S-EPMC7755099 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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An Irreversible Inhibitor to Probe the Role of <i>Streptococcus pyogenes</i> Cysteine Protease SpeB in Evasion of Host Complement Defenses.

Woehl Jordan L JL   Kitamura Seiya S   Dillon Nicholas N   Han Zhen Z   Edgar Landon J LJ   Nizet Victor V   Wolan Dennis W DW  

ACS chemical biology 20200728 8


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 <i>Streptococcus pyogenes</i> and implicated in the pathogenesis of the bacterium through degradation of key human immune effector proteins. Here, we developed and characterized a clickable inhibitor, <b>2</b><i><b>S</b></i><b>-alkyne</b>, based on X-ray crystallographic analysis and structure-activity relationships. Our Spe  ...[more]

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