“AT1R antagonists may be life-saving for acutely ill SARS-CoV-2-infected patients”
Common cold vs Covid-19 – 8:26 min
Treatments of Covid-19 should aim at:
1) preventing the virus from entering the cell
2) while preventing ACE2 deficiency at the same time
Current treatments don’t match both criteria. AT1R antagonists do.
As a group of doctors and researchers, we believe that AT1R antagonists, such as Candesartan, Losartan or Valsartan, might provide substantial clinical benefit to acutely ill SARS-CoV-2-infected patients. These drugs have a good safety profile, are widely available and inexpensive.
They should be tested without delay.
This is why AT1R antagonists might work:
The renin-angiotensin system lies at the heart of the response to respiratory infections. It involves angiotensin II (AngII), a vasoconstrictor and pro-inflammatory factor, and a membrane-associated regulatory mechanism: angiotensin converting enzyme 2 (ACE2) and angiotensin II type 1 receptor (AT1R). ACE2 inactivates AngII and AT1R inhibits ACE2. The system is self-regulating. If the infection calls for a stronger inflammatory reaction, AT1R directs ACE2 removal and AngII continues to exert its effects. When infection subsides, ACE2 is no longer removed. Instead, it cleaves AngII into Angiotensin 1-7, which has vasodilating, anti-inflammatory actions, the opposite of AngII.
SARS-CoV-2 infects epithelial cells in the respiratory tract by binding to the ACE2-AT1R complex. Upon binding, it is endocytosed, and the virus is released in the cytoplasm. Normally, ACE2-AT1R endocytosis leads to intracellular production of nitrous oxide (NO). NO inhibits AT1R-activated ACE2 degradation and primes an adaptive immune response, specific for the pathogen. But SARS-CoV-2 disrupts the normal ACE2/AngII balance: NO is absent, adaptive immunity is not primed and AngII accumulates, resulting in life-threatening cytokine storms. SARS-CoV-2 causes acute pulmonary disease through a vicious circle: more ACE2-AT1R lead to higher viral loads, more ACE2-AT1R endocytosis and AngII-driven inflammation
- Why not Chloroquine? Chloroquine disrupts the glycosylation of ACE2 and inhibits its endocytosis. However, it also likely inhibits ACE2-driven conversion of AngII to Ang (1-7), needed for NO production and adaptive immunity.
- Why not recombinant ACE2? Excess exogenous ACE2 may well capture SARS-CoV-2 outside cells, locally. But ACE2 is an important regulator of smooth muscle relaxation and neurotransmission. Excess systemic ACE2 raises serious safety concerns.
- Why not antiviral drugs? Antiviral drugs disrupt the cycle of infection at various stages. However, they do not support the development of adaptive immunity and, in the case of SARS-CoV-2, do not protect from reinfection, as has been observed.
- Why not Tocilizumab? Toculizimab inhibits IL-6, a pro-inflammatory cytokine which activates AngII. Inhibiting IL-6 may not be expected to preserve ACE2 functions.
AT1R inhibition would prevent the entry of SARS-CoV-2 inside the cell, without inactivating ACE2 activity which is anti-inflammatory, nor disrupting ACE2 regulation of vital processes. ARB’s (angiotensin receptor blockers) as are cheap, widely available and safe. As a growing group of doctors and researchers, we believe ARB’s should be tested in acutely ill SARS-CoV-2-infected patients without delay. Doctors may consider AT1R antagonists as a Covid-19 treatment and share their experiences.
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