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 Goodwin; Allan Jacobson; Slobodan Paessler; Stuart W Peltz

doi:10.1016/j.virusres.2020.198246

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

Virus Res. 2021 Jan 15:292:198246. doi: 10.1016/j.virusres.2020.198246. Epub 2020 Nov 26.

Authors

Jeremy Luban¹, Rachel A Sattler², Elke Mühlberger³, Jason D Graci⁴, Liangxian Cao⁴, Marla Weetall⁴, Christopher Trotta⁴, Joseph M Colacino⁴, Sina Bavari⁵, Caterina Strambio-De-Castillia⁶, Ellen L Suder⁷, Yetao Wang⁶, Veronica Soloveva⁵, Katherine Cintron-Lue⁴, Nikolai A Naryshkin⁴, Mark Pykett⁴, Ellen M Welch⁴, Kylie O'Keefe⁴, Ronald Kong⁴, Elizabeth Goodwin⁴, Allan Jacobson⁸, Slobodan Paessler², Stuart W Peltz⁹

Affiliations

¹ 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, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA.
² Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA.
³ 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.
⁴ PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA.
⁵ United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, 21702, USA.
⁶ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
⁷ Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, 02118, USA.
⁸ Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
⁹ PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA. Electronic address: speltz@ptcbio.com.

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.

Keywords: Antiviral; COVID-19; Coronavirus; Cytokine; Cytokine storm; DHODH; PTC299; SARS-CoV-2.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antiviral Agents / pharmacology*
COVID-19 Drug Treatment
Carbamates / pharmacology*
Carbazoles / pharmacology*
Chlorocebus aethiops
Cytokine Release Syndrome / drug therapy
Cytokines / antagonists & inhibitors*
Cytokines / immunology
Dihydroorotate Dehydrogenase
HeLa Cells
Humans
Inflammation / drug therapy
Inflammation / virology
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
SARS-CoV-2 / drug effects*
Vero Cells
Virus Replication / drug effects*

Substances

Antiviral Agents
Carbamates
Carbazoles
Cytokines
Dihydroorotate Dehydrogenase
emvododstat
Oxidoreductases Acting on CH-CH Group Donors

Abstract

Publication types

MeSH terms

Substances

Grants and funding