SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development

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Nicholas Murgolo1, Alex G Therien2, Bonnie Howell3

  • 1Department of Genetics and Pharmacogenomics, Merck & Co., Inc., Kenilworth, New Jersey, United States of America.

Plos Pathogens
|February 17, 2021
PubMed

Insights

Drug repurposing screens show promise for COVID-19 treatments, but using non-human cell lines raises questions about real-world effectiveness. Further research is needed to develop better in vitro models for drug discovery.

Area of Science:

  • Virology
  • Infectious Diseases
  • Drug Discovery

Background:

  • Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19, a global pandemic with a wide spectrum of disease severity.
  • Current FDA-approved treatments for COVID-19 are limited, with remdesivir being the only one.
  • Early therapeutic strategies have focused on drug repurposing to find existing compounds with antiviral activity against SARS-CoV-2.

Purpose of the Study:

  • To discuss the key molecular and cellular interactions in SARS-CoV-2 infection.
  • To provide a framework for developing an appropriate in vitro toolbox for drug discovery.
  • To address the limitations of current drug repurposing screens using non-human cell lines.

Main Methods:

  • Review of current understanding of SARS-CoV-2 molecular and cellular interactions.
  • Analysis of drug repurposing screens for antiviral compounds.
  • Evaluation of the physiological and pathological relevance of in vitro models.

Main Results:

  • Drug repurposing screens have identified potential antiviral compounds.
  • The use of non-human immortalized cell lines presents challenges in predicting clinical efficacy.
  • There is a need for more physiologically relevant in vitro models.

Conclusions:

  • Understanding SARS-CoV-2 infection mechanisms is crucial for effective drug development.
  • Improved in vitro models are essential to support current and future drug discovery efforts for COVID-19.
  • Further research should focus on validating drug candidates in more relevant cellular systems.

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