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

PLoS Pathog. 2021 Feb 17;17(2):e1009225. doi: 10.1371/journal.ppat.1009225. eCollection 2021 Feb.


Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • COVID-19 / virology
  • COVID-19 Drug Treatment
  • Cathepsins
  • Cell Line
  • Drug Development
  • Drug Discovery*
  • Endocytosis
  • Furin
  • Humans
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / physiology*
  • Serine Endopeptidases
  • Viral Tropism*
  • Virus Internalization*
  • Virus Replication*


  • Cathepsins
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • FURIN protein, human
  • Furin

Grant support

This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.The authors are employees of Merck and Co., Inc., and were responsible for the study design, data collection and analysis, decision to publish, and preparation of the manuscript.