Drug combination therapy for emerging viral diseases

Abstract

Effective therapeutics to combat emerging viral infections are an unmet need. Historically, treatments for chronic viral infections with single drugs have not been successful, as exemplified by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections. Combination therapy for these diseases has led to improved clinical outcomes with dramatic reductions in viral load, morbidity, and mortality. Drug combinations can enhance therapeutic efficacy through additive, and ideally synergistic, effects for emerging and re-emerging viruses, such as influenza, severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS)-CoV, Ebola, Zika, and SARS-coronavirus 2 (CoV-2). Although novel drug development through traditional pipelines remains a priority, in the interim, effective synergistic drug candidates could be rapidly identified by drug-repurposing screens, facilitating accelerated paths to clinical testing and potential emergency use authorizations.

Keywords: COVID-19; Drug combination therapy; Emerging viral diseases; SARS-CoV-2.

Figure 1

Therapeutic targets for HIV, HCV and influenza. (a) US Food and Drug Administration (FDA)-approved therapeutic interventions for HIV infection. Attachment inhibitors, postattachment inhibitors, CCR5 inhibitors, and fusion inhibitors serve as viral entry inhibitors. Other antivirals include antiretrovirals nucleoside/non-nucleoside reverse transcriptase inhibitors (NRTIs/NNRTIs), integrase strand transfer inhibitors (INSTIs), and protease inhibitors (PIs). Pharmacokinetic enhancers (PKEs) can also be used in combination with other drugs. Combination antiretroviral therapy (cART) generally comprises two NRTI drugs plus one or more drugs from other categories (see also Table 1 in the main text). (b) Therapeutic targets for the treatment of hepatitis C virus (HCV) infections. Treatment of HCV usually comprises combinations of two or more drugs from the following categories: NS3/4 PIs, NS5A inhibitors, and NS5B polymerase inhibitors (see also Table 1 in the main text). Treatment regimens vary depending on different clinical parameters. As an example, initial treatment for a simple, drug-naïve HCV infection can include a combination of sofobuvir + velpatasvir (NS5B polymerase inhibitor + NS5A inhibitor) for 12 weeks or glecaprevir + pibrentasvir (NS3/4 PI + NS5A inhibitor) for 8 weeks.(c) Current approved drug targets against influenza (A and B) virus. Combination drugs are being tested in clinical trials but have not yet been approved (see also Table 1 in the main text).

Figure 2

Schematic workflows of drug combination screening. (a) Pooled method to screen two-drug combinations. Responses of multiple ten-drug pools were examined in the primary test. Each effective pool was deconvoluted and tested as 45 two-drug combinations to reveal effective drug pairs. (b) Screening three-drug combinations by fixing the concentration of two drugs. In this method, the dose response of a third drug was investigated with or without a fixed dose of two drugs, such as drug A and B. The presence of drug A and B might result in the dose–response curve of the third drug shifting to the left, increase potency (as shown for drug C in the figure), or lead to no significant change (as shown for drug H in the figure). Combinations with increased potency can be further tested. (c) Matrix method to screen two-drug combinations. Effects of a given drug pair can be examined in a 6 × 6 matrix format. The matrix comprises a series of dilution concentrations of one drug (example drug A) in each column and a series of dilution concentrations of another drug (example drug B) in each row. Results can then be analyzed based on different models. A Highest Single Agent (HSA) model was used as a representation here. The matrix method can reveal effective drug pairs, as well as the concentration of each drug that gives the greatest synergistic effect.