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

针对药物诱导耐药性的新型抗流感药物：基于机制的神经氨酸酶抑制剂

• 批准号: G0600514/1
• 负责人: Andrew Watts
• 金额: $ 52.04万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0600514%2F1
• 关键词: Novel; Anti; Influenza; Agents; Target

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.

我们的研究重点是尝试开发一类改进的抗病毒药物来治疗流感病毒，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与当前流感药物瑞乐沙（Relenza）和达菲（Tamiflu）相关的一些问题。不幸的是，Relenza 的临床用途因其不能口服给药而降低，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。Relenza 和达菲通过阻止释放来发挥作用。来自受感染细胞的新形成的病毒颗粒。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附着在已感染细胞的表面，并且无法逃脱以感染更多细胞。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，我们相信；我）。对我们的化合物产生耐药性的可能性要小得多，并且 ii)。还应该可以在这些抑制剂中引入化学特征，使其能够口服给药。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，它们还可以让我们更好地了解流感病毒如何产生抗病毒药物耐药性。