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.
- 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.
- Recombinant ACE2 administered either systemically or locally to the
lungs may help replenish ACE2 and restore balance to the tipped RAS
axis.
- 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.