Broadening COVID-19 Interventions to Drug Innovation: Neprilysin Pathway as a Friend, Foe, or Promising Molecular Target?

OMICS. 2021 Jul;25(7):408-416. doi: 10.1089/omi.2021.0080. Epub 2021 Jun 30.


The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is anticipated to transition to an endemic state as vaccines are providing relief in some, but not all, countries. Drug discovery for COVID-19 can offer another tool in the fight against the pandemic. Additionally, COVID-19 impacts multiple organs that call for a systems medicine approach to planetary health and therapeutics innovation. In this context, innovation for drugs that prevent and treat COVID-19 is timely and much needed. As the virus variants emerge under different ecological conditions and contexts in the long haul, a broad array of vaccine and drug options will be necessary. This expert review article argues for a need to expand the COVID-19 interventions, including and beyond vaccines, to stimulate discovery and development of novel medicines against SARS-CoV-2 infection. The Renin-Angiotensin-Aldosterone System (RAAS) is known to play a major role in SARS-CoV-2 infection. Neprilysin (NEP) and angiotensin-converting enzyme (ACE) have emerged as the pharmaceutical targets of interest in the search for therapeutic interventions against COVID-19. While the NEP/ACE inhibitors offer promise for repurposing against COVID-19, they may display a multitude of effects in different organ systems, some beneficial, and others adverse, in modulating the inflammation responses in the course of COVID-19. This expert review offers an analysis and discussion to deepen our present understanding of the pathophysiological function of neprilysin in multiple organs, and the possible effects of NEP inhibitor-induced inflammatory responses in COVID-19-infected patients.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; bradykinin storm; cytokine storm; drug discovery; neprilysin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bradykinin / genetics
  • Bradykinin / metabolism
  • Neprilysin / chemistry*
  • Renin-Angiotensin System / genetics
  • Renin-Angiotensin System / physiology
  • SARS-CoV-2


  • Neprilysin
  • Bradykinin