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

Fang Li, Chunlong Ma, William F. Degrado, Jun Wang

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

With the emergence of highly pathogenic avian influenza (HPAI) H7N9 and H5N1 strains, there is a pressing need to develop direct-acting antivirals (DAAs) to combat such deadly viruses. The M2-S31N proton channel of the influenza A virus (A/M2) is one of the validated and most conserved proteins encoded by the current circulating influenza A viruses; thus, it represents a high-profile drug target for therapeutic intervention. We recently discovered a series of S31N inhibitors with the general structure of adamantyl-1-NH2+CH2-aryl, but they generally had poor physical properties and some showed toxicity in vitro. In this study, we sought to optimize both the adamantyl as well as the aryl/heteroaryl group. Several compounds from this study exhibited submicromolar EC50 values against S31N-containing A/WSN/33 influenza viruses in antiviral plaque reduction assays with a selectivity index greater than 100, indicating that these compounds are promising candidates for in-depth preclinical pharmacology.

Original languageEnglish (US)
Pages (from-to)1207-1216
Number of pages10
JournalJournal of Medicinal Chemistry
Volume59
Issue number3
DOIs
StatePublished - Feb 11 2016

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Influenza A virus
Drug Delivery Systems
Antiviral Agents
Protons
Influenza in Birds
Orthomyxoviridae
Pharmacology
Viruses
Pharmaceutical Preparations
Proteins
Therapeutics
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of Highly Potent Inhibitors Targeting the Predominant Drug-Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel. / Li, Fang; Ma, Chunlong; Degrado, William F.; Wang, Jun.

In: Journal of Medicinal Chemistry, Vol. 59, No. 3, 11.02.2016, p. 1207-1216.

Research output: Contribution to journalArticle

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