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Optimization of 4‑Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir
journal contribution
posted on 2020-02-28, 21:32 authored by 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 RongVaccination 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.