Drug repurposing for COVID-19: Approaches, challenges and promising candidates

Abstract

Traditional drug development and discovery has not kept pace with threats from emerging and re-emerging diseases such as Ebola virus, MERS-CoV and more recently, SARS-CoV-2. Among other reasons, the exorbitant costs, high attrition rate and extensive periods of time from research to market approval are the primary contributing factors to the lag in recent traditional drug developmental activities. Due to these reasons, drug developers are starting to consider drug repurposing (or repositioning) as a viable alternative to the more traditional drug development process. Drug repurposing aims to find alternative uses of an approved or investigational drug outside of its original indication. The key advantages of this approach are that there is less developmental risk, and it is less time-consuming since the safety and pharmacological profile of the repurposed drug is already established. To that end, various approaches to drug repurposing are employed. Computational approaches make use of machine learning and algorithms to model disease and drug interaction, while experimental approaches involve a more traditional wet-lab experiments. This review would discuss in detail various ongoing drug repurposing strategies and approaches to combat the current COVID-19 pandemic, along with the advantages and the potential challenges.

Keywords: Antivirals; COVID-19; Clinical Trials; Drug Repurposing; Emerging Viruses.

Fig. 1

List of FDA-approved antiviral drugs from 2015 to 2020. From 2015 to 2020, 15 novel antiviral drugs have been approved for treatment against hepatitis C virus (HCV), smallpox, influenza, ebola virus (EBOV), human immunodeficiency virus (HIV) and recently, for severe acute respiratory virus coronavirus 2 (SARS-CoV-2). The majority of new drugs approved are for HCV and HIV. The active pharmaceutical ingredient, brand name and biopharmaceutical company that manufactures these drugs are indicated accordingly.

Fig. 2

Approaches to drug repurposing. Drug repurposing approaches can be broadly divided into computational and experimental approaches. Here, computational approaches may be used individually or in combination to analyse COVID-19 disease pathogenesis to obtain useful information for screening putative COVID-19 drug candidates in the experimental approach. The vector images have been designed using resources from Flaticon.com.

Fig. 3

Overview of investigational antiviral drugs for SARS-CoV-2 targeting the various stages of the virus life cycle. SARS-CoV-2 infections are typically initiated by the binding of the spike (S) protein to the ACE2 receptor decorated on the surface of the target cell. With the help of the TMPRSS2 protein, the S protein undergoes a series of conformational changes to allow membrane fusion and release of the viral genome into the host cytoplasm. Once the viral genome is released into the host cytoplasm, protein translation quickly ensues to produce the replicase proteins pp1a and pp1ab. Proteolytic processing of pp1a and pp1ab sets the stage for the assembly of the replicase-transcriptase complex for the replication and transcription of the viral genome and subgenomic RNAs. Protein products of the translated RNAs in the endoplasmic reticulum will be transported into the endoplasmic-reticulum Golgi intermediate complex (ERGIC) for virus assembly. The virus is then transported in vesicles for egress by exocytosis. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine 2; pp1a, polyprotein 1a; pp1ab, polyprotein 1ab.