Fight flu with mechanism-based covalent neuraminidase inhibitors

The development of resistance to commonly used antiviral drugs Relenza and Tamiflu has become a serious problem facing the world. It is reported that 98 percent of influenza A/H1N1 strains in North America are resistant to Tamiflu. The Withers group has designed a series of sialic acid analogs in which the C-2 OH group was replaced with fluoride to trap the virus by the formation of a covalent intermediate. To slow down the reactivation rates of neuraminidase, an electronegative flurorine was introduced at C-3 position to destabilize the positively charged transition state en-route to the formation and hydrolysis of the covalent intermediate. In addition, to confer specificity for the influenza neuraminidase over human sialidases, a positively charged nitrogen substituent was incorporated by analogy with the design of Relenza and Tamiflu. Those compounds showed very promising properties against the influenza virus.

Dr. Zhizeng Gao proposes to take advantage of the mechanism of action of this class of inhibitors, and develop a set of fluorescent and fluorogenic neuraminidase probes. Such probes share structural similarities with the inhibitor but the fluorine at C-2 was replaced with latent fluorophores, or C-7-OH was linked with fluorophores. Such probes are useful for investigation of the presence and role of neuraminidases in biological systems, especially if their presence or activity can be detected, quantitated and in some cases localized.