Recent progress in designing inhibitors that target the drug‐resistant M2 proton channels from the influenza A viruses

Abstract

Influenza viruses are the causative agents for seasonal influenza, which results in thousands of deaths and millions of hospitalizations each year. Moreover, sporadic transmission of avian or swan influenza viruses to humans often leads to an influenza pandemic, as there is no preimmunity in the human body to fight against such novel strains. The metastable genome of the influenza viruses, coupled with the reassortment of different strains from a wide range of host origins, leads to the continuous evolution of the influenza virus diversity. Such characteristics of influenza viruses present a grand challenge in devising therapeutic strategies to combat influenza virus infection. This review summarizes recent progress in designing small molecule inhibitors that target the drug-resistant influenza A virus M2 proton channels and highlights the contribution of mechanistic studies of proton conductance to drug discovery. The lessons learned throughout the course of M2 drug discovery might provide insights for designing inhibitors that target other therapeutically important ion channels.

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

“…With the aim of developing novel anti-influenza drugs, we chose the M2 proton channel as the drug target because M2 is one of the most conserved viral proteins (Dong et al, 2015; Wang, 2016; Wang et al, 2015; Wang et al, 2011c). Although many M2 mutants emerged under drug selection pressure in cell cultures (Abed et al, 2005; Brown et al, 2010), animals (Herlocher et al, 2003), and human patients (Hayden and Hay, 1992; Iwahashi et al, 2001), only a few of them acquired the fitness to transmit among humans (Dong et al, 2015; Furuse et al, 2009a; Furuse et al, 2009b).…”

Design and expeditious synthesis of organosilanes as potent antivirals targeting multidrug-resistant influenza A viruses

“…[20] The prevalence of this mutation thus makes AM2-S31N a desired target for drug design. [21] Propelled by structural and mechanistic understandings of AM2 proton conductance and drug inhibition,[21, 22] we successfully designed the first-in-class AM2-S31N inhibitors with both potent channel blockage and antiviral activity. [21, 23–26] Encouraged by this progress, in this study we report the design and expeditious synthesis of organosilane-based AM2-S31N inhibitors.…”

Discovery of Highly Potent Inhibitors Targeting the Predominant Drug-Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel

“…13 This small set of transmissible mutants suggests that M2 is a highly conserved drug target compared with other viral proteins, rendering it an ideal drug target for the development of anti-influenza drugs. 21 However, drug discovery targeting M2 has been hampered by the lack of a reliable high-throughput screening assay and high-resolution structures. Nevertheless, guided by information gathered from molecular dynamics simulations, 22,23 X-ray crystallography, 24,25 and solution- and solid-state NMR spectroscopy, 22,26,27 recent years have witnessed significant progress in this area, and several classes of compounds have been shown to inhibit all three major drug resistant mutants: V27A, L26F, and S31N.…”