COVID-19 Outbreak Overview &

the Link between SARS-CoV-2 & AT1R Antagonists

What Is COVID-19?

Over the course of just a few months, the severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, responsible for the COVID-19 outbreak, has caused chaos worldwide.

With over 150,000 confirmed cases (as of March 2020) and close to 6,000 deaths, the World Health Organization (WHO) has rightfully declared a state of emergency5.

SARS-CoV-2 Receptor Recognition

With the race to discovering a vaccine is well underway, observations indicate that Angiotensin-converting enzyme 2 (ACE2) is the likely binding site for SARS-CoV-21,3, similar to that of SARS-CoV-2 (Figure 1). ACE2 is a type I membrane protein responsible for cleaving Angiotensin II (Ang II) to the heptapeptide Angiotensin (1-7), (Ang (1-7))4.

SARS-CoV-2 structure.
Figure 1: SARS-CoV-2 virus uses angiotensin-converting enzyme 2 (ACE2) as its host cell entry receptor.

ACE2 Signaling

ACE and its close homolog ACE2 have opposing actions. ACE increases levels of Ang II by cleaving Ang I, which ultimately leads to increased blood pressure through its binding to Angiotensin II Receptor Type-1 (AT1R). ACE2 on the other hand, decreases Ang II levels by generating the vasodilator Ang (1-7), which then acts through the MAS receptor2.

Extensive studies on the predecessor of SARS-CoV-2 show that binding of the virus to ACE2 causes downregulation of the protein, resulting in an increase in ACE expression, and therefore Ang II. These increases ultimately lead to over-stimulation of AT1R, reflected by higher pulmonary vascular permeability and a sustained inflammatory response2.

Treating SARS-CoV-2 patients with AT1R antagonists, such as Losartan (#L-185) or Olmesartan (#O-125) may be a means to increase ACE2 in order to counteract the virus’ effects. Thus, higher ACE2 expression following AT1R antagonist administration could counteract the increased levels of Ang II which could in turn be converted to Ang (1-7)2.

References

  1. Chen, Y. et al. (2020) Biophys. Res. Commun. DOI: 10.1016/j.bbrc.2020.02.071.
  2. Gurwitz, D. (2020) Drug Dev. Res. DOI: 10.1002/ddr.21656.
  3. Lu, R. et al. (2020) Lancet 395,
  4. Warner, F.J. et al. (2005) Biol. Chem. 280, 39353.
  5. https://www.who.int/

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