An Irreversible Inhibitor to Probe the Role of Streptococcus pyogenes Cysteine Protease SpeB in Evasion of Host Complement Defenses.
ACS Chem Biol
; 15(8): 2060-2069, 2020 08 21.
Article
en En
| MEDLINE
| ID: mdl-32662975
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Streptococcus pyogenes
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Proteínas Bacterianas
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Inhibidores de Cisteína Proteinasa
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Proteasas de Cisteína
Idioma:
En
Revista:
ACS Chem Biol
Año:
2020
Tipo del documento:
Article