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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Feb 19

PMID 32069052

Citations 10

Authors

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

Affiliations

Soon will be listed here.

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 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 showed significant synergistic activity with oseltamivir in vitro.

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