2. Academic Validation
  3. Prodrugs of a 1'-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV

Prodrugs of a 1'-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV

  • J Med Chem. 2021 Apr 22;64(8):5001-5017. doi: 10.1021/acs.jmedchem.1c00071.
Richard L Mackman 1,  Hon C Hui 1,  Michel Perron 1,  Eisuke Murakami 1,  Christopher Palmiotti 1,  Gary Lee 1,  Kirsten Stray 1,  Lijun Zhang 1,  Bindu Goyal 1,  Kwon Chun 1,  Daniel Byun 1,  Dustin Siegel 1,  Scott Simonovich 1,  Venice Du Pont 1,  Jared Pitts 1,  Darius Babusis 1,  Arya Vijjapurapu 1,  Xianghan Lu 1,  Cynthia Kim 1,  Xiaofeng Zhao 1,  Julie Chan 1,  Bin Ma 1,  Diane Lye 1,  Adelle Vandersteen 1,  Sarah Wortman 1,  Kimberly T Barrett 1,  Maria Toteva 1,  Robert Jordan 1,  Raju Subramanian 1,  John P Bilello 1,  Tomas Cihlar 1
Affiliations

Affiliation

  • 1 Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 33835812 DOI: 10.1021/acs.jmedchem.1c00071
Abstract

A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.

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