Combination Therapy with UV-4B and Molnupiravir Enhances SARS-CoV-2 Suppression

Author:

Franco Evelyn J.12,Drusano George L.1,Hanrahan Kaley C.1,Warfield Kelly L.3,Brown Ashley N.12ORCID

Affiliation:

1. Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL 32827, USA

2. Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA

3. Emergent BioSolutions, Gaithersburg, MD 20879, USA

Abstract

The host targeting antiviral, UV-4B, and the RNA polymerase inhibitor, molnupiravir, are two orally available, broad-spectrum antivirals that have demonstrated potent activity against SARS-CoV-2 as monotherapy. In this work, we evaluated the effectiveness of UV-4B and EIDD-1931 (molnupiravir’s main circulating metabolite) combination regimens against the SARS-CoV-2 beta, delta, and omicron BA.2 variants in a human lung cell line. Infected ACE2 transfected A549 (ACE2-A549) cells were treated with UV-4B and EIDD-1931 both as monotherapy and in combination. Viral supernatant was sampled on day three when viral titers peaked in the no-treatment control arm, and levels of infectious virus were measured by plaque assay. The drug–drug effect interaction between UV-4B and EIDD-1931 was also defined using the Greco Universal Response Surface Approach (URSA) model. Antiviral evaluations demonstrated that treatment with UV-4B plus EIDD-1931 enhanced antiviral activity against all three variants relative to monotherapy. These results were in accordance with those obtained from the Greco model, as these identified the interaction between UV-4B and EIDD-1931 as additive against the beta and omicron variants and synergistic against the delta variant. Our findings highlight the anti-SARS-CoV-2 potential of UV-4B and EIDD-1931 combination regimens, and present combination therapy as a promising therapeutic strategy against SARS-CoV-2.

Funder

Institute for Therapeutic Innovation, University of Florida

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

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