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.
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2022-10
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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.
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Demarest, James F, Maryline Kienle, RuthMabel Boytz, Mary Ayres, Eun Jung Kim, JJ Patten, Donghoon Chung, Varsha Gandhi, et al. (2022). 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. Antiviral research, 206. p. 105403. 10.1016/j.antiviral.2022.105403 Retrieved from https://hdl.handle.net/10161/31840.
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Scholars@Duke
James Francis Demarest
I have >30 years of experience in the pre-clinical, clinical, and translational research space. Twenty-three of those years are in the pharma R&D context where I also gained experience in diagnostics, product commercialization and life-cycle management, interactions with Regulatory Authorities, Key Opinion Leaders (globally), and establishment/maintenance of public-private partnerships. My career trajectory took me from NIH (Dr. Anthony Fauci’s laboratory), to Duke University, to GlaxoWellcome/GSK, ViiV Healthcare, AbbVie Immunology and consultancies. I was a founding member of the scientific and medical organization at ViiV Healthcare (launched in Nov 2009; www.viivhealthcare.com ) and contributed significantly to shaping its evolving strategy and associated success. I know from firsthand experience the technical and business aspects of building a successful company delivering medicines that meet unmet medical needs. Through my involvement with establishment/launch of collaborations via public-private partnerships and/or business development, I understand what pharma companies expect from partnerships with biotech and/or academia. I have also worked closely with the medical affairs and commercial/marketing organizations on numerous international, regional, and local market projects/campaigns. I bring this breadth of experience to advance innovative approaches for R&D.
The following highlights my general skill set and experience:
R&D Innovation:
- Led and supported research programs, translational research teams, and impact(ed) the business strategy for building a forward-looking R&D pipeline; small molecule, biologic, and vaccine platforms
- Co-developed governance processes to safely expedite compound progression from discovery through clinical development
- Accountable for virology data packages included in 4 successful approvals and global launches (TIVICAY, TRIUMEQ, JULUCA, and DOVATO) and updates to inflammatory bowel disease indications for Humira
- Applying expertise to advancing preventative and therapeutic approaches for SARS-CoV-2 infection and antiviral medical countermeasures
Business Development:
- Subject matter expert for in-licensing review and advisory role informing business development strategy for pre-clinical and clinical R&D platforms/assets and diagnostics
- Member of Integration teams post deal closure
- Advisor for academic-based biotech and entrepreneurial start-ups
Strategic Partnerships:
- Defined and launched multi-year/multi-million-dollar global research collaborations with key academic institutions, including integrated analyses of laboratory generated data with longitudinal patient clinical data
- Initiated, led, or supported in vitro, pre-clinical, and clinical phase global research studies
Commercialization:
- Scientific lead or advisor for commercial/marketing and medical affairs efforts associated with product launches and life cycle management
Diagnostics:
- Directed diagnostic collaborations associated with investigative agents or marketed products
- Provided technical advice for assays and algorithms used in clinical care across diverse geographic regions
Regulatory:
- Written and face-to-face interactions with regulatory authorities pre- and post-market authorization
Scientific Communication:
- Explaining disease area science and medicine mechanisms of action to a broad spectrum of audiences, ranging from key opinion leaders to clinicians/scientists to patient advocates to the lay public
- Graduate and Medical Student mentoring at Duke University
- Freshman Experience Course co-creator/co-lecturer at High Point University
- UNCW OLLI and Duke OLLI invited lecturer
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