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Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine.
Hulce, Kaitlin R; Jaishankar, Priyadarshini; Lee, Gregory M; Bohn, Markus-Frederik; Connelly, Emily J; Wucherer, Kristin; Ongpipattanakul, Chayanid; Volk, Regan F; Chuo, Shih-Wei; Arkin, Michelle R; Renslo, Adam R; Craik, Charles S.
  • Hulce KR; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Jaishankar P; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Lee GM; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Bohn MF; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Connelly EJ; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Wucherer K; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Ongpipattanakul C; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Volk RF; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Chuo SW; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Arkin MR; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Renslo AR; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
  • Craik CS; Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA. Electronic address: charles.craik@ucsf.edu.
Cell Chem Biol ; 29(5): 785-798.e19, 2022 05 19.
Article en En | MEDLINE | ID: mdl-35364007
ABSTRACT
Viruses are responsible for some of the most deadly human diseases, yet available vaccines and antivirals address only a fraction of the potential viral human pathogens. Here, we provide a methodology for managing human herpesvirus (HHV) infection by covalently inactivating the HHV maturational protease via a conserved, non-catalytic cysteine (C161). Using human cytomegalovirus protease (HCMV Pr) as a model, we screened a library of disulfides to identify molecules that tether to C161 and inhibit proteolysis, then elaborated hits into irreversible HCMV Pr inhibitors that exhibit broad-spectrum inhibition of other HHV Pr homologs. We further developed an optimized tool compound targeted toward HCMV Pr and used an integrative structural biology and biochemical approach to demonstrate inhibitor stabilization of HCMV Pr homodimerization, exploiting a conformational equilibrium to block proteolysis. Irreversible HCMV Pr inhibition disrupts HCMV infectivity in cells, providing proof of principle for targeting proteolysis via a non-catalytic cysteine to manage viral infection.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Infecciones por Citomegalovirus / Citomegalovirus Límite: Humans Idioma: En Año: 2022 Tipo del documento: Article
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Infecciones por Citomegalovirus / Citomegalovirus Límite: Humans Idioma: En Año: 2022 Tipo del documento: Article