Drug Targets
Therapeutically, upstream regulation of RAS using aliskiren or global RAS blockade with a combination of ACEi and ARBs have not shown many benefits.36 This has been studied in the context of chronic low-grade activation of the RAS axis. A different strategy may be required in the case of a RAS-crisis or acute RAS dysregulation. The following drug targets may be viable in the setting of severe COVID-19 infections.
  1. The upsurge of Angiotensin II due to acute ACE2 downregulation in COVID-19 would cause a shift in the prorenin/renin balance. Blocking the alternative pathway of RAS activation in the form of prorenin receptor antagonists will help in curbing alternate pathways of inflammation in the dysregulated RAS situation.
  2. Recombinant ACE2 administered either systemically or locally to the lungs may help replenish ACE2 and restore balance to the tipped RAS axis.
  3. RAS inhibition in the form of ACE inhibitors and ARBs have shown inconsistent effects in the presentation and course of COVID-19. This is because the RAS effects of the available drugs is different. This is due to the differences in the pharmacokinetics and pharmacodynamic properties of the different drugs. In the setting of an acute RAS dysfunction, we believe that global RAS blockade may help curb the excessive inflammation due to the RAS positive feedback loop.
While the initiation of the pathogenesis occurs because of the viral replication, severe cases occur due to severe immune system dysfunction. We insist that the RAS axis plays a major role in the immune dysregulation and may be targeted in the treatment of COVID-19.