Title

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

UMMS Affiliation

Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology; Department of Microbiology and Physiological Systems

Publication Date

2021-01-15

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Enzymes and Coenzymes | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Immunotherapy | Infectious Disease | Microbiology | Molecular Biology | Virus Diseases

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

DOI of Published Version

10.1016/j.virusres.2020.198246

Source

Luban J, Sattler RA, Mühlberger E, Graci JD, Cao L, Weetall M, Trotta C, Colacino JM, Bavari S, Strambio-De-Castillia C, Suder EL, Wang Y, Soloveva V, Cintron-Lue K, Naryshkin NA, Pykett M, Welch EM, O'Keefe K, Kong R, Goodwin E, Jacobson A, Paessler S, Peltz SW. The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines. Virus Res. 2020 Nov 26;292:198246. doi: 10.1016/j.virusres.2020.198246. Epub ahead of print. PMID: 33249060; PMCID: PMC7690341. Link to article on publisher's site

Journal/Book/Conference Title

Virus research

Comments

This article is based on a previously available preprint on bioRxiv that is also available in eScholarship@UMMS.

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

33249060

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