Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS)

Med Hypotheses. 2020 Oct;143:110112. doi: 10.1016/j.mehy.2020.110112. Epub 2020 Jul 16.

Abstract

In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.

Keywords: ACE2; COVID-19; Pandemic; SARS-CoV-2; Spironolactone; TMPRS22.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgen Antagonists / therapeutic use*
  • Androgens / physiology*
  • Angiotensin-Converting Enzyme 2
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Betacoronavirus / physiology*
  • COVID-19
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use
  • Coronavirus Infections / complications
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / epidemiology
  • Coronavirus Infections / physiopathology
  • Enzyme Induction / drug effects
  • Humans
  • Hypertension / complications
  • Hypertension / drug therapy
  • Hypertension / physiopathology
  • Kidney / drug effects
  • Male
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Mineralocorticoid Receptor Antagonists / therapeutic use*
  • Obesity / complications
  • Obesity / physiopathology
  • Pandemics*
  • Peptidyl-Dipeptidase A / biosynthesis
  • Peptidyl-Dipeptidase A / drug effects
  • Pneumonia, Viral / complications
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / epidemiology
  • Pneumonia, Viral / physiopathology
  • Prognosis
  • Receptors, Virus / drug effects
  • Renin-Angiotensin System / drug effects*
  • Risk Factors
  • SARS-CoV-2
  • Serine Endopeptidases / drug effects
  • Sex Distribution
  • Spironolactone / pharmacology
  • Spironolactone / therapeutic use*
  • Virus Internalization / drug effects

Substances

  • Androgen Antagonists
  • Androgens
  • Angiotensin-Converting Enzyme Inhibitors
  • Cardiotonic Agents
  • Mineralocorticoid Receptor Antagonists
  • Receptors, Virus
  • Spironolactone
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Supplementary concepts

  • COVID-19 drug treatment