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

Journal of Medicinal Chemistry
Fang LiJun Wang

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.

References

May 1, 1992·Cell·L H PintoR A Lamb
Apr 25, 2000·Annual Review of Medicine·N J Cox, K Subbarao
Jan 9, 2003·JAMA : the Journal of the American Medical Association·William W ThompsonKeiji Fukuda
May 15, 1964·Science·W L DAVIESC E HOFFMANN
Sep 16, 2004·JAMA : the Journal of the American Medical Association·William W ThompsonKeiji Fukuda
Dec 2, 2006·Nature Reviews. Drug Discovery·Erik De Clercq
Jun 17, 2008·Nature Chemical Biology·Jay W SchneiderJenny Hsieh
Jul 18, 2008·Journal of Medicinal Chemistry·Joie GarfunkleDale L Boger
Jan 16, 2009·Proceedings of the National Academy of Sciences of the United States of America·Ekta KhuranaMichael L Klein
Aug 7, 2010·Proceedings of the National Academy of Sciences of the United States of America·Rudresh AcharyaMichael L Klein
Nov 19, 2010·The New England Journal of Medicine·Linda C Lambert, Anthony S Fauci
Nov 26, 2010·European Journal of Medicinal Chemistry·Xin ZhaoWenhui Hu
Jan 21, 2011·Current Opinion in Structural Biology·Jun WangWilliam F DeGrado
Mar 29, 2011·Expert Opinion on Pharmacotherapy·Paolo Preziosi
Apr 7, 2011·Journal of Medicinal Chemistry·María D DuqueSantiago Vázquez
Aug 9, 2011·Journal of the American Chemical Society·Jun WangWilliam F DeGrado
Oct 29, 2011·The Lancet Infectious Diseases·Michael T OsterholmEdward A Belongia
Jul 4, 2012·Nature Reviews. Microbiology·José Luis NievaLuis Carrasco
Sep 25, 2012·Protein Science : a Publication of the Protein Society·Mei Hong, William F DeGrado
Jan 11, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jun WangWilliam F Degrado
Jan 19, 2013·Annual Review of Medicine·Natalie Pica, Peter Palese
Apr 16, 2013·Antiviral Research·Nick S Laursen, Ian A Wilson
Jul 5, 2013·Clinical Microbiology Reviews·Sook-San Wong, Richard J Webby
Jun 4, 2014·Annals of the New York Academy of Sciences·Robert G Webster, Elena A Govorkova

❮ Previous
Next ❯

Citations

Jul 19, 2017·International Journal of Molecular Sciences·Wandi ZhuBao-Zhong Wang
Jul 3, 2019·Cells·Janet To, Jaume Torres
Aug 25, 2020·Chemistry of Heterocyclic Compounds·Vadim A Shiryaev, Yuri N Klimochkin
Dec 10, 2016·Journal of the American Chemical Society·Salomé LlabrésF Javier Luque
Nov 16, 2018·ACS Medicinal Chemistry Letters·Yanmei HuJun Wang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.