A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-molecule BCG Mimics to Prevent COVID-19 Mortality

Abstract

Purpose: Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops ‘herd immunity’, or until a vaccine is developed and used as a prevention. However, the vaccine may prove ineffective due to rapid changes in viral antigenic determinants. Bacillus Calmette–Guérin (BCG) vaccine has been recognized for its off-target beneficial effects on the immune system, therefore, can be exploited to boast immunity and protect from emerging novel viruses.Methods: We developed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and impact a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses. Results: We show that BCG affect the production and maturation of naïve T cells, which results in enhanced long-lasting trained innate immune responses to tackle novel viruses. Our workflow identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, top hits emetine and lopinavir were validated to inhibit the growth of SARS-CoV-2 in vitro.Conclusions: Our results provide systems biology support for using BCG and small-molecule BCG mimics as a protection measure from the lethal consequences of emergent viruses including SARS-CoV-2.