Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds

Abstract

We here report on the synthesis of new series of polycyclic amines initially designed as ring-rearranged analogs of amantadine and featuring pentacyclo, hexacyclo, and octacyclo rings. A secondary amine, 3-azahexacyclo[7.6.0.0¹,⁵.0⁵,¹².0⁶,¹⁰.0¹¹,¹⁵]pentadeca-7,13-diene, 3, effectively inhibited A/M2 proton channel function, and, moreover, possessed dual activity against an A/H3N2 virus carrying a wild-type A/M2 proton channel, as well as an amantadine-resistant A/H1N1 virus. Among the polycyclic amines that did not inhibit influenza A/M2 proton channel function, several showed low-micromolar activity against tested A/H1N1 strains (in particular, the A/PR/8/34 strain), but not A/H3N2 influenza viruses. A/PR/8/34 mutants selected for resistance to these compounds possessed mutations in the viral hemagglutinin that markedly increased the hemolysis pH. Our data suggest that A/H1N1 viruses such as the A/PR/8/34 strain are particularly sensitive to a subtle increase in the endosomal pH, as caused by the polycyclic amine compounds.

Keywords: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; Amantadine; Amt; CPE; HA; HRMS; Hemagglutinin; Influenza A virus; M2 protein; MDCK; MTS; Madin–Darby canine kidney; N-methyl-d-aspartate; NMDA; Polycyclic amines; TEV; TM; amantadine; cytopathic effect; hemagglutinin; high resolution mass spectra; transmembrane; two-electrode voltage clamps; wild-type; wt.