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Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection
Chang-ki Oh; Tomohiro Nakamura; Nathan Beutler; Xu Zhang; Juan Pina-Crespo; Maria Talantova; Swagata Ghatak; Dorit Trudler; Lauren N. Carnevale; Scott R. McKercher; Malina A. Bakowski; Jolene K. Diedrich; Amanda J. Roberts; Ashley K. Woods; Victor Chi; Anil K. Gupta; Mia A. Rosenfeld; Fiona L. Kearns; Lorenzo Casalino; Namir Shaabani; Hejun Liu; Ian A. Wilson; Rommie E. Amaro; Dennis R. Burton; John R. Yates III; Cyrus Becker; Thomas F. Rogers; Arnab K. Chatterjee; Stuart A. Lipton.
Afiliación
  • Chang-ki Oh; The Scripps Research Institute
  • Tomohiro Nakamura; The Scripps Research Institute
  • Nathan Beutler; The Scripps Research Institute
  • Xu Zhang; The Scripps Research Institute
  • Juan Pina-Crespo; The Scripps Research Institute
  • Maria Talantova; The Scripps Research Institute
  • Swagata Ghatak; The Scripps Research Institute
  • Dorit Trudler; The Scripps Research Institute
  • Lauren N. Carnevale; The Scripps Research Institute
  • Scott R. McKercher; The Scripps Research Institute
  • Malina A. Bakowski; The Scripps Research Institute
  • Jolene K. Diedrich; The Scripps Research Institute
  • Amanda J. Roberts; Scripps Research Institute
  • Ashley K. Woods; The Scripps Research Institute
  • Victor Chi; The Scripps Research Institute
  • Anil K. Gupta; The Scripps Research Institute
  • Mia A. Rosenfeld; University of California, San Diego
  • Fiona L. Kearns; University of California, San Diego
  • Lorenzo Casalino; University of California, San Diego
  • Namir Shaabani; The Scripps Research Institute
  • Hejun Liu; The Scripps Research Institute
  • Ian A. Wilson; The Scripps Research Institute
  • Rommie E. Amaro; University of California, San Diego
  • Dennis R. Burton; The Scripps Research Institute
  • John R. Yates III; The Scripps Research Institute
  • Cyrus Becker; EuMentis Therapeutics, Inc.
  • Thomas F. Rogers; The Scripps Research Institute
  • Arnab K. Chatterjee; The Scripps Research Institute
  • Stuart A. Lipton; The Scripps Research Institute and University of California, San Diego, School of Medicine
Preprint en En | PREPRINT-BIORXIV | ID: ppbiorxiv-487060
ABSTRACT
Prevention of infection and propagation of SARS-CoV-2 is of high priority in the COVID-19 pandemic. Here, we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 Spike protein, thereby inhibiting viral entry, infectivity, and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and thus spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E-protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model, and thus provide a novel avenue for therapy.
Licencia
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Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2022 Tipo del documento: Preprint
Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2022 Tipo del documento: Preprint