COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

Robert E Malone ,Chad J Roy,Assaf Alon,Philip Fremont-Smith,Joshua Pottel,Elena Moreno,Nora Smith,Gideon Shapiro,Julie M Hall,Yongfeng Liu,Bryan L Roth,Andrew C Kruse,Anthony Mittermaier,Philip Tisdall,Guanyu Wang,Jill Glasspool-Malone,Lisa Miorin,Kris M White,Darrell O Ricke,Elise Delaforge,Xi Ping Huang ,Kevin M Tomera ,Adolfo Garcı́a-Sastre ,Christopher Hennecker ,Robert V Blair

doi:10.3389/fphar.2021.633680

Abstract

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.

Highlights

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) is a highly infectious and pathogenic betacoronavirus first detected in human infections during December 2019 (Wu D. et al, 2020; Wu and McGoogan, 2020; Zhu et al, 2020)
Famotidine Does Not Bind to SARS-CoV-2 Proteases Initial testing of famotidine as a medical countermeasure for COVID-19 emerged from a computational molecular docking effort aimed at identifying inhibitors of the papain-like protease (PLpro) of SARS-CoV-2 (Baez-Santos et al, 2015; Daczkowski et al, 2017)
A previous virtual screening report (Wu C. et al, 2020) suggested that famotidine might bind to the 3 chymotrypsin-like protease (3CLpro), more commonly referred to as the main protease (Mpro), this mechanism was recently discounted (Anson et al, 2020)

Summary

Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) is a highly infectious and pathogenic betacoronavirus first detected in human infections during December 2019 (Wu D. et al, 2020; Wu and McGoogan, 2020; Zhu et al, 2020). Coronavirus infectious disease—2019 (COVID-19) is a disease spectrum causally associated with infection by SARS-CoV-2. Definitive COVID-19 diagnosis requires the presence of the virus, which can be isolated, grown, or otherwise detected as unique SARS-CoV-2 viral nucleic acid sequences. There are SARS-CoV-2 virus shedding or nucleic acid positive patients that do not manifest clinical COVID-19 (Danis et al, 2020; Furukawa et al, 2020; Ki and Task Force for -nCo, 2020; Lai et al, 2020; Pan et al, 2020; Zou et al, 2020). SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease

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