From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus.

Elnaz Aledavood,Carolina Estarellas,Matteo Masetti,Beatrice Selmi,F Javier Luque

doi:10.3389/fmolb.2021.796229

Elnaz Aledavood, Carolina Estarellas + Show 3 more

Open Access

https://doi.org/10.3389/fmolb.2021.796229

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Abstract

With an estimated 1 billion people affected across the globe, influenza is one of the most serious health concerns worldwide. Therapeutic treatments have encompassed a number of key functional viral proteins, mainly focused on the M2 proton channel and neuraminidase. This review highlights the efforts spent in targeting the M2 proton channel, which mediates the proton transport toward the interior of the viral particle as a preliminary step leading to the release of the fusion peptide in hemagglutinin and the fusion of the viral and endosomal membranes. Besides the structural and mechanistic aspects of the M2 proton channel, attention is paid to the challenges posed by the development of efficient small molecule inhibitors and the evolution toward novel ligands and scaffolds motivated by the emergence of resistant strains.

Highlights

Influenza A virus is an important pathogen that still causes the death of 290,000–650,000 people in seasonal outbreaks worldwide (Iuliano et al, 2018)
Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (HA), which is responsible for the receptor binding and membrane fusion, and neuraminidase (NA), which assists the release of the viral progeny (Cheung and Poon, 2007)
Resistance to current pharmacological treatments is a severe health challenge, as illustrated by the emergence of viral strains resistant to drugs interfering with the M2 proton channel, such as Amt and Rmt, and to antiviral agents targeting neuraminidase, such as oseltamivir, as noticed in a resistant strain associated to the His275Tyr mutation in this protein (Meijer et al, 2009; Ginex and Luque, 2021)

Summary

Introduction

Influenza A virus is an important pathogen that still causes the death of 290,000–650,000 people in seasonal outbreaks worldwide (Iuliano et al, 2018). It pertains to the Orthomyxoviridae family, which is characterized by the presence of a negative-sense, single-stranded, enveloped ribonucleic acid with a segmented genome (Cheung and Poon, 2007). Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (HA), which is responsible for the receptor binding and membrane fusion, and neuraminidase (NA), which assists the release of the viral progeny (Cheung and Poon, 2007). Some subtypes (H1N1, H2N2, H3N2, H5N1, H7N7, and H9N2) have been isolated from humans, suggesting that there are restrictions to host viruses in humans

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