Optimization of 4-Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir

Irina N. Gaisina, Norton P. Peet, Han Cheng, Ping Li, Ruikun Du, Qinghua Cui, Kevin Furlong, Balaji Manicassamy, Michael Caffrey, Gregory R.J. Thatcher, Lijun Rong

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for the acute treatment of influenza infections to control this virus and prevent epidemics/pandemics from developing. We have discovered fast-acting, orally bioavailable acylated 4-aminopiperidines with an effective mechanism of action targeting viral hemagglutinin (HA). Our data show that these compounds are potent entry inhibitors of influenza A viruses. We present docking studies that suggest an HA binding site for these inhibitors on H5N1. Compound 16 displayed a significant decrease of viral titer when evaluated in the infectious assays with influenza virus H1N1 (A/Puerto Rico/8/1934) or H5N1 (A/Vietnam/1203/2004) strains and the oseltamivir-resistant strain with the most common H274Y mutation. In addition, compound 16 showed significant synergistic activity with oseltamivir in vitro.

Original languageEnglish (US)
Pages (from-to)3120-3130
Number of pages11
JournalJournal of Medicinal Chemistry
Volume63
Issue number6
DOIs
StatePublished - Mar 26 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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