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

Jordan L. Woehl, Seiya Kitamura, Nicholas Dillon, Zhen Han, Landon J. Edgar, Victor Nizet, Dennis W. Wolan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2060-2069
Number of pages10
JournalACS Chemical Biology
Volume15
Issue number8
DOIs
StatePublished - Aug 21 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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