Rational Repurposing of Drugs, Clinical Trial Candidates, and Natural Products for SARS-CoV-2 Therapy

In the last 20 years, the world has been threatened with coronavirus (CoV) pandemic threats from severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 and finally COVID-19 due to SARS-CoV-2 in 2019. These viruses posed serious global pandemic threats, with estimated case fatality rates of 15% for SARS-CoV, 34% for MERS-CoV, and 1-3% for SARS-CoV-2. With the current pandemic still far from over there is an urgent need to find new drug treatments for COVID-19. We can assume that this will not be the last coronavirus to threaten humanity, so we need better tools to identify drugs active against past but also future coronavirus threats. In this Chapter we describe in silico computer modeling and screening approaches that can rapidly identify drugs from existing drug libraries that could be repurposed to treat COVID-19 infections. We also describe how this computational screening pipeline can be expanded in the future to identify drugs with broad spectrum activity against a wide diversity of coronaviruses. A significant concern is that the protection against CoVs provided by single drugs protection may be short-lived because viruses rapidly mutate to develop drug resistance. We know from other viruses such as HIV that drugs hitting multiple targets within the virus provide better protection against the development of resistance. This Chapter describes the current state of development of in silico CoV drug repurposing, the challenges and pitfalls of these approaches, and our predictions of how these methods could be used to develop drugs for future pandemics before they occur.