A substrate mimetic approach for influenza neuraminidase inhibitors

Over recent years increased understanding of the influenza virus replication cycle has allowed investigators to identify several potential molecular targets for drug design. The crystal structures of two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), expressed by both influenza A and B viruses have been determined and well characterized. These results have encouraged basic research for the development of specific and potent inhibitors of HA and NA. The infection cycle of influenza virus starts in the surface epithelial cells of the respiratory tract. HA mediate the binding of virus to the host cell via terminal sialic acid residue in glycoconjugates and the process of endocytosis. NA, a glycohydrolase, removes the sialic acid from glycoconjugates and facilitates the release of the virus particles from the infected cell surfaces during the budding processes and this prevents aggregation of virions by removing sialic acid residues from viral glycoproteins. Inhibition of viral replication step should be an effective method to control and potentially to eradicate viruses from infected tissues. Therefore, inhibition of the viral neuraminidase should prevent the influenza virus replication and NA has been considered to be a suitable target for designing drugs against influenza viruses. Since the discovery that N-acetylneuraminic acid 1 (NANA) had inhibitory activity against NA, a novel analog, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid 2 (DANA), was synthesized with 1,000 times more activity than NANA. DANA is considered as a transition state-like analogue binding to the active site of NA. On the basis of structural information generated from the X-ray crystallographic study, rationally designed guanidino analogue zanamivir 3 was also active and launched with the name of Relenza. However, because of its poor oral bioavailibility and rapid excretion, zanamivir is administered only by nasal inhalation. Recently, a new class of compounds having a chemically versatile carbocyclic ring in place of the dihydropyran ring of DANA was developed as another transition-state mimic by Gilead Sciences. In this series oseltamivir 4 (Tamiflu) was highly active with good oral bioavailibility, which has been in clinical use since 1999. Contrary to this progress, we designed compound 5 for the comparative study of a substrate-mimetic approach to the transition-state mimics. For this study a carbocyclic ring was