Brequinar and dipyridamole in combination exhibits synergistic antiviral activity against SARS-CoV-2 in vitro: Rationale for a host-acting antiviral treatment strategy for COVID-19.

Autor: Demarest JF; Clear Creek Bio, Cambridge, MA, USA., Kienle M; Clear Creek Bio, Cambridge, MA, USA., Boytz R; NEIDL, Boston University, Boston, MA, USA., Ayres M; Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA., Kim EJ; University of Louisville, Louisville, KY, USA., Patten JJ; NEIDL, Boston University, Boston, MA, USA., Chung D; University of Louisville, Louisville, KY, USA., Gandhi V; Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA., Davey RA; NEIDL, Boston University, Boston, MA, USA., Sykes DB; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA., Shohdy N; Clear Creek Bio, Cambridge, MA, USA., Pottage JC Jr; Clear Creek Bio, Cambridge, MA, USA., Kumar VS; Clear Creek Bio, Cambridge, MA, USA. Electronic address: brq@clearcreekbio.com.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2022 Oct; Vol. 206, pp. 105403. Date of Electronic Publication: 2022 Aug 28.
DOI: 10.1016/j.antiviral.2022.105403
Abstrakt: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the associated global pandemic resulting in >400 million infections worldwide and several million deaths. The continued evolution of SARS-CoV-2 to potentially evade vaccines and monoclonal antibody (mAb)-based therapies and the limited number of authorized small-molecule antivirals necessitates the need for development of new drug treatments. There remains an unmet medical need for effective and convenient treatment options for SARS-CoV-2 infection. SARS-CoV-2 is an RNA virus that depends on host intracellular ribonucleotide pools for its replication. Dihydroorotate dehydrogenase (DHODH) is a ubiquitous host enzyme that is required for de novo pyrimidine synthesis. The inhibition of DHODH leads to a depletion of intracellular pyrimidines, thereby impacting viral replication in vitro. Brequinar (BRQ) is an orally available, selective, and potent low nanomolar inhibitor of human DHODH that has been shown to exhibit broad spectrum inhibition of RNA virus replication. However, host cell nucleotide salvage pathways can maintain intracellular pyrimidine levels and compensate for BRQ-mediated DHODH inhibition. In this report, we show that the combination of BRQ and the salvage pathway inhibitor dipyridamole (DPY) exhibits strong synergistic antiviral activity in vitro against SARS-CoV-2 by enhanced depletion of the cellular pyrimidine nucleotide pool. The combination of BRQ and DPY showed antiviral activity against the prototype SARS-CoV-2 as well as the Beta (B.1.351) and Delta (B.1.617.2) variants. These data support the continued evaluation of the combination of BRQ and DPY as a broad-spectrum, host-acting antiviral strategy to treat SARS-CoV-2 and potentially other RNA virus infections.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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