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The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines.
Luban, Jeremy; Sattler, Rachel A; Mühlberger, Elke; Graci, Jason D; Cao, Liangxian; Weetall, Marla; Trotta, Christopher; Colacino, Joseph M; Bavari, Sina; Strambio-De-Castillia, Caterina; Suder, Ellen L; Wang, Yetao; Soloveva, Veronica; Cintron-Lue, Katherine; Naryshkin, Nikolai A; Pykett, Mark; Welch, Ellen M; O'Keefe, Kylie; Kong, Ronald; Goodwin, Elizabeth; Jacobson, Allan; Paessler, Slobodan; Peltz, Stuart W.
  • Luban J; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01605, USA; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA, 02142
  • Sattler RA; Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA.
  • Mühlberger E; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA; Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, 02118, USA.
  • Graci JD; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Cao L; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Weetall M; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Trotta C; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Colacino JM; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Bavari S; United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, 21702, USA.
  • Strambio-De-Castillia C; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
  • Suder EL; Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, 02118, USA.
  • Wang Y; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
  • Soloveva V; United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, 21702, USA.
  • Cintron-Lue K; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Naryshkin NA; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Pykett M; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Welch EM; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • O'Keefe K; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Kong R; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Goodwin E; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
  • Jacobson A; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
  • Paessler S; Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA.
  • Peltz SW; PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA. Electronic address: speltz@ptcbio.com.
Virus Res ; 292: 198246, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-974719
Preprint
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ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Carbamates / Carbazoles / Cytokines / Oxidoreductases Acting on CH-CH Group Donors / SARS-CoV-2 Limits: Animals / Humans Language: English Journal: Virus Res Journal subject: Virology Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Carbamates / Carbazoles / Cytokines / Oxidoreductases Acting on CH-CH Group Donors / SARS-CoV-2 Limits: Animals / Humans Language: English Journal: Virus Res Journal subject: Virology Year: 2021 Document Type: Article