Title: Role of ACE2 glycosylation and Rho kinase inhibition in the infective and therapeutic process of COVID-19
CoV-2 cellular entry that could lead to a new therapeutic approach.
It’s well known that the infection is due to the viral binding with the ACE2 receptor. ACE2 is glycosylated in the endosomes, Golgi vesicles and lysosomes, a process driven by the acidic intracellular environment, essential for the viral binding. In fact, the prophylactic/therapeutic use of chloroquine and other antimalarial drugs finds its rationale in their effect of increasing intracellular pH, leading to the production of unglycosylated ACE2 and likely reduction/inhibition of the infection.
Several studies have reported both the protective role of ACE2 in SARS-CoV-2-induced Acute Distress Syndrome (ARDS), the leading cause of death from COVID-19 and a relationship between Rho kinase (ROCK), ARDS and increased ACE2 levels induced by ROCK inhibitors.
Using circulating mononuclear cells from Gitelman’s and Bartter’s syndrome patients (GS/BS) (rare genetic tubulopathies), who have increased ACE2 expression, metabolic alkalosis (not favorable for viral binding), increased and related ACE2 and Ang 1-7 levels and reduced ROCK activity, we aim to evaluate ex vivo in these patients the glycosylation state of ACE2.
A telephone survey on more than 100 GS/BS from the hotspots of COVID-19 pandemic in Northern Italy (Veneto, Lombardia, Emilia Romagna) showed that none of GS/BS reported infection or symptoms of COVID-19. This could be a significant evidence of how an increase of ACE2 levels and a reduction of ROCK activity could be useful in the prevention/treatment of COVID-19.
Our objective is to demonstrate the role of ACE2 glycosylation in the infective process of SARS-CoV2, the potential prophylactic/therapeutic role of molecules/drugs that interfere with ACE2 glycosylation and the demonstration ex vivo in humans the protective role of ROCK inhibition.