Low-dose fluvoxamine modulates endocytic trafficking of SARS-CoV-2 spike protein: a potential mechanism for anti-COVID-19 protection by antidepressants

Abstract

Commonly prescribed antidepressants may be associated with protection against severe COVID-19, with one drug (fluvoxamine) currently undergoing a Phase 3 clinical trial. The mechanism of their action, however, remains unknown. Here, I investigated the effect of fluvoxamine on membrane trafficking of the SARS-CoV-2 spike protein and its cell host receptor ACE2 in HEK293T cells. A sub-therapeutic concentration (80 nM) of fluvoxamine rapidly upregulated fluid-phase endocytosis, resulting in enhanced accumulation of the spike-ACE2 complex in enlarged early endosomes. Diversion of endosomal trafficking provides a simple cell biological mechanism consistent with the protective effect of antidepressants against COVID-19, highlighting their therapeutic and prophylactic potential.

Combination Therapies against COVID-19

“…Since it was established that SARS-CoV-2 infection could induce the activation of tissue factormediated coagulation via activation of acid sphingomyelinase [91], and blockage of acid sphingomyelinase prevented uptake of SARS-CoV-2 by epithelial cells [92], targeting the acid sphingomyelinase is a promising strategy to combat COVID-19. Fluoxetine and fluvoxamine are well studied inhibitors of acid sphingomyelinase and show great therapeutic potential for SARS-CoV-2 infection [93][94][95].…”