Antiviral Drug Combinations for Treatment of Emerging and Re-emerging Viral Infections

Today, combination antiviral therapy is one of the main methods of treatment of complex diseases, such as HIV, HCV and HBV. Antiviral drug combinations have advantages over monotherapies because of their greater efficacy, less toxicity, and their ability to combat coinfections or multiple viral agents at the same time. Moreover, monotherapy is more often associated with a high rate of viral drug resistance than treatment with multiple drugs. In this thesis, we contribute to the development of combination antiviral therapy from two directions. First, we study novel antiviral combinations with synergistic effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis C virus (HCV), human immunodeficiency virus 1 (HIV-1) and echovirus 1 (EV1) in vitro. Secondly, we develop a database of antiviral drug combinations showing synergistic or additive effects against different types of human viruses. As the result of the experimental work, we discovered that combinations of nelfinavir and convalescent serum, EIDD-2801, remdesivir, salinomycin, amodiaquine, homoharringtonine, or obatoclax showed synergistic activity against SARS-CoV-2 in human lung epithelial cells Calu-3, as well as a combination of amodiaquine plus salinomycin. We also detected that combinations of sofosbuvir plus brequinar or niclosamide are synergistic against HCV infection in Huh-7.5 cell culture. Also, we found that lamivudine-monensin and tenofovir-monensin combinations are synergistic against HIV-1 infection in human cervical TZM-bl cell line. In addition, we figured out that FDA-approved anti-cancer drug vemurafenib is an effective inhibitor of EV1. Finally, we observed synergistic antiviral activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. These results reveal that a synergistic effect is achieved when an antiviral agent targeting a virus is combined with another compound targeting a virus or a host. As the result of the development of antiviral drug combination database, we included almost 1000 antiviral combinations and covered 612 unique drugs and 68 different viruses and presented a detailed statistics of development stages of each drug combination. This database is aimed to significantly help researchers and experienced physicians to reduce time in identifying new promising combinations based on already conducted studie

Identification and Tracking of Antiviral Drug Combinations

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.Peer reviewe

Potential Antiviral Options against SARS-CoV-2 Infection. Viruses.

As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19