The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines

Jeremy Luban, Rachel A. Sattler, Elke Mühlberger, Jason D. Graci, Liangxian Cao, Marla Weetall, Christopher Trotta, Joseph M. Colacino, Sina Bavari, Caterina Strambio-De-Castillia, Ellen L. Suder, Yetao Wang, Veronica Soloveva, Katherine Cintron-Lue, Nikolai A. Naryshkin, Mark Pykett, Ellen M. Welch, Kylie O'Keefe, Ronald Kong, Elizabeth GoodwinAllan Jacobson, Slobodan Paessler, Stuart W. Peltz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number198246
JournalVirus Research
Volume292
DOIs
StatePublished - Jan 15 2021

Keywords

  • Antiviral
  • Coronavirus
  • COVID-19
  • Cytokine
  • Cytokine storm
  • DHODH
  • PTC299
  • SARS-CoV-2

ASJC Scopus subject areas

  • Cancer Research
  • Virology
  • Infectious Diseases

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