TY - JOUR
T1 - Discovery of Highly Potent Inhibitors Targeting the Predominant Drug-Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel
AU - Li, Fang
AU - Ma, Chunlong
AU - Degrado, William F.
AU - Wang, Jun
N1 - Funding Information:
This research is supported by NIH Grant AI119187 and the PhRMA foundation 2015 research starter grant in pharmacology and toxicology to J.W., and NIH Grants GM056423 and AI74571 to W.F.D.
PY - 2016/2/11
Y1 - 2016/2/11
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.5b01910
DO - 10.1021/acs.jmedchem.5b01910
M3 - Article
C2 - 26771709
AN - SCOPUS:84958213343
VL - 59
SP - 1207
EP - 1216
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -