Identification and Tracking of Antiviral Drug Combinations

Abstract

Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status.

Interferon alpha-based combinations suppress SARS-CoV-2 infection in vitro and in vivo

“…We also tested IFNa2a in combination with known anti-retrovirals agents, lamivudine, brequinar, tenofovir, suramin, clofarabine and decitabine [40–43] against HIV-1 in TZM-bl cells. Cell viability and HIV-induced luciferase expression were measured for each compound or their combination with IFNa2a after 48 h. We identified that IFNa2a and lamivudine in combination was most effective while being nontoxic at synergistic drug concentrations, with ZIP synergy scores of 5.7 and ZIP synergy score of 11.4 at the most synergistic area (Fig.…”

“…The propagation of wild-type SARS-CoV-2 (hCoV-19/Norway/Trondheim-S15/2020), recombinant mCherry-expressing SARS-CoV-2 strains (SARS-CoV-2-mCherry), wild type human influenza A/Udorn/307/1972 (H3N2) and HIV-1 have been also described previously [22, 40–43](Rihn et al, PBIOLOGY-D-20-02646R2). To quantitate the production of infectious virions, we titered the viruses using plaque assays or ELISA [22, 40–43].…”

Screening of FDA-approved drugs using a MERS-CoV clinical isolate from South Korea identifies potential therapeutic options for COVID-19

“…The observed responses were compared to expected combination responses. The expected responses were calculated based on the zero interaction potency (ZIP) reference model using SynergyFinder version 2 [17]. Briefly, the degree of combination synergy, or antagonism, is quantified by comparing the observed drug combination response against the expected response, calculated using a reference model that assumes no interaction between drugs.…”

Synergistic Interferon Alpha-based Drug Combinations Inhibit SARS-CoV-2 and other viral Infections in Vitro

“…The convalescent serum (G614) obtained from a recovered COVID-19 patient has been described in a previous study [22]. HIV-1 provirus) using firefly luciferase assay, have been described in our previous studies [22,[40][41][42][43].…”

“…The propagation of wild-type SARS-CoV-2 (hCoV-19/Norway/Trondheim-S15/2020), recombinant mCherry-expressing SARS-CoV-2 strains (SARS-CoV-2-mCherry), wild type human influenza A/Udorn/307/1972 (H3N2) and HIV-1 have been also described previously [22,[40][41][42][43](Rihn et al,…”