Repurposing Fragile X Drugs to Inhibit SARS-CoV-2 Viral Reproduction.

Cara J Westmark,Yoshihiro Kawaoka,Maki Kiso,Pamela R Westmark,Peter Halfmann

doi:10.3389/fcell.2020.00856

Abstract

The COVID-19 pandemic is a global health crisis that requires the application of interdisciplinary research to address numerous knowledge gaps including molecular strategies to prevent viral reproduction in affected individuals. In response to the Frontiers Research Topic, “Coronavirus disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management, and Public Health Response,” this Hypothesis article proposes a novel therapeutic strategy to repurpose metabotropic glutamate 5 receptor (mGluR5) inhibitors to interfere with viral hijacking of the host protein synthesis machinery. We review pertinent background on SARS-CoV-2, fragile X syndrome (FXS) and metabotropic glutamate receptor 5 (mGluR5) and provide a mechanistic-based hypothesis and preliminary data to support testing mGluR5 inhibitors in COVID-19 research.

Highlights

In December of 2019, an outbreak of respiratory disease began in Wuhan, China
Inhibition of metabotropic glutamate receptor 5 (mGluR5) represses exaggerated protein synthesis that occurs in the absence of the RNA binding protein fragile X mental retardation protein (FMRP) (Bear et al, 2004; Osterweil et al, 2010)
We propose that inclusion of mGluR5 Negative allosteric modulators (NAMs) as part of a drug cocktail approach to combat COVID-19 offers the advantages of: (1) extensive preclinical research regarding its mechanism of action; (2) prior safety testing in human clinical trials of fragile X syndrome (FXS); (3) numerous mGluR5 NAMs available from multiple pharmaceutical countries worldwide; (4) orally dosed; (5) protein target ubiquitously expressed including the lungs; (6) less expensive to produce small molecule drugs; and (7) targets a post-transcriptional gene regulatory step in viral production not addressed by other therapies under investigation

Summary

Introduction

In December of 2019, an outbreak of respiratory disease began in Wuhan, China. The causative agent was a novel betacoronavirus of the same subgenus as severe acute respiratory syndrome (SARS) coronavirus (CoV) and was named SARS-CoV-2, a.k.a. novel CoV (nCoV-2019), which causes the disease coronavirus-19 (COVID-19) (Zhu et al, 2020). Molecular Modeling Predicts That FMRP Binds to SARS-CoV-2 Positive and Negative Sense RNAs

Results

Conclusion