tetano
Editor, Senior Moderator
J Med Chem. 2020 Feb 18. doi: 10.1021/acs.jmedchem.9b01900. [Epub ahead of print] [h=1]Optimization of 4-aminopiperidines as inhibitors of influenza A viral entry that are synergistic with oseltamivir.[/h]
Gaisina IN, Peet N, Cheng H, Li P, Du R, Cui Q, Furlong K, Manicassamy B, Caffrey M, Thatcher GR, Rong L.
[h=3]Abstract[/h] 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/PuertoRico/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.
PMID: 32069052 DOI: 10.1021/acs.jmedchem.9b01900
Gaisina IN, Peet N, Cheng H, Li P, Du R, Cui Q, Furlong K, Manicassamy B, Caffrey M, Thatcher GR, Rong L.
[h=3]Abstract[/h] 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/PuertoRico/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.
PMID: 32069052 DOI: 10.1021/acs.jmedchem.9b01900