Interactions of SARS-CoV-2 spike protein and transient receptor potential (TRP) cation channels could explain smell, taste, and/or chemesthesis disorders

TL;DR

This study explores how SARS-CoV-2 spike protein may interact with TRP cation channels, potentially explaining sensory disorders like loss of smell and taste in COVID-19 patients, through molecular docking and hypothesis.

Contribution

It proposes a novel mechanism where SARS-CoV-2 spike protein interacts with TRP channels, affecting their function and contributing to sensory symptoms in COVID-19.

Findings

SARS-CoV-2 S protein contains ankyrin repeat binding motifs.

Docking suggests S protein interacts with TRPA1, TRPV1, and TRPV4 channels.

Interactions may interfere with channel assembly and trafficking.

Abstract

A significant subset of patients infected by SARS-CoV-2 presents olfactory, taste, and/or chemesthesis (OTC) disorders (OTCD). These patients recover rapidly, eliminating damage of sensory nerves. Discovering that S protein contains two ankyrin repeat binding motifs (S-ARBMs) and some TRP cation channels, implicated in OTC, have ankyrin repeat domains (TRPs-ARDs), I hypothesized that interaction of S-ARBMs and TRPs-ARDs could dysregulate the function of the latter and thus explains OTCD. Of note, some TRPs-ARDs are expressed in the olfactory epithelium, taste buds, trigeminal neurons in the oronasal cavity and vagal neurons in the trachea/lungs. Furthermore, this hypothesis is supported by studies that have shown: (i) respiratory viruses interact with TRPA1 and TRPV1 on sensory nerves and epithelial cells in the airways, (ii) the respiratory pathophysiology in COVID-19 patients is similar to lungs injuries produced by the sensitization of TRPV1 and TRPV4, and (iii) resolvin D1 and D2 shown to reduce SARS-CoV-2-induced inflammation, directly inhibit TRPA1, TRPV1, TRPV3 and TRPV4. Herein, results of blind dockings of S-ARBMs, 408-RQIAPG-413 (in RBD but distal from the ACE-2 binding region) and 905-RFNGIG-910 (in HR1), into TRPA1, TRPV1 and TRPV4 suggest that S-ARBMs interact with ankyrin repeat 6 of TRPA1 near an active site, and ankyrin repeat 3-4 of TRPV1 near cysteine 258 supposed to be implicated in the formation of inter-subunits disulfide bond. These findings suggest that S-ARBMs affect TRPA1, TRPV1 and TRPV4 function by interfering with channel assembly and trafficking. After an experimental confirmation of these interactions, among possible preventive treatments against COVID-19, the use of pharmacological manipulation (probably inhibition) of TRPs-ARDs to control or mitigate sustained pro-inflammatory response.