Novel Anti Influenza Agents to Target Drug-Induced Resistance: Mechanism-based Neuraminidase Inhibitors

我们的研究重点是试图开发一种改进的抗病毒药物，用于治疗流感病毒，包括高致病性禽H5N1（禽流感）流感病毒。我们将开发的化合物旨在克服目前流感药物Relenza和Tamiflu的一些问题。不幸的是，瑞乐沙的临床效用因其不能口服而降低，最令人担忧的是，在一些感染H5N1病毒的患者中已经观察到药物诱导的对达菲的耐药性。瑞乐沙和达菲的作用是防止新形成的病毒颗粒从感染细胞中释放出来。它们通过阻断一种称为神经氨酸酶的特定酶的作用来实现这一点，因此被称为神经氨酸酶抑制剂。如果神经氨酸酶被阻断（抑制），新形成的病毒颗粒仍然附着在已感染细胞的表面，并且无法逃脱以感染其他细胞。我们正在开发的化合物也是神经氨酸酶抑制剂，但抑制酶的方式与瑞乐沙和达菲非常不同。通过以不同的方式抑制神经氨酸酶，我们认为：i）。对我们的化合物的耐药性不太可能发展，和ii）。还应该可以将化学特征引入这些抑制剂中，以允许它们口服给药。最终，我们希望证明我们的神经氨酸酶抑制剂是治疗流感的合适靶点，它们也应该让我们更好地了解流感病毒如何对抗病毒药物产生耐药性。

Our research is focused on trying to develop an improved class of anti-virals for the treatment of influenza viruses, including the highly pathogenic avian H5N1 (Bird Flu) influenza virus. The compounds we will be developing are designed to overcome some of the problems associated with the current influenza drugs, Relenza and Tamiflu. Unfortunately, the clinical usefulness of Relenza is reduced by the fact that it cannot be administered orally and, most alarmingly, drug-induced resistance to Tamiflu has already been observed in some patients infected with the H5N1 virus.Relenza and Tamiflu act by preventing the release of newly formed virus particles from infected cells. They do this by blocking the action of a particular enzyme known as a neuraminidase, and hence, are referred to as neuraminidase inhibitors. If the neuraminidase is blocked (inhibited), newly formed virus particles remain attached to the surface of already infected cells, and are unable to escape to infect further cells. The compounds we are developing are also neuraminidase inhibitors, but inhibit the enzyme in a very different way to Relenza and Tamiflu. By inhibiting the neuraminidase in a different way, we believe that; i). resistance to our compounds is much less likely to develop, and ii). it should also be possible to introduce chemical features into these inhibitors that will allow them to be administered orally. Ultimately, we hope to show that our neuraminidase inhibitors are suitable targets for the treatment of influenza, and they should also give us a much better understanding of how influenza viruses develop resistance to anti-viral drugs.