Design and Development of Inhibitors of the Dengue Virus Protease as Antiviral Drugs

登革热病毒由蚊子携带，感染世界各地数百万人，特别是在东南亚、中美洲和南美洲、非洲的热带国家，最近在澳大利亚（北昆士兰州和新台币）。没有疫苗或药物可用于预防或治疗感染，其特征是严重的疾病，涉及炎症和发烧，有时可能是致命的。该建议集中于病毒特异性酶。这种酶（称为蛋白酶）是病毒繁殖所必需的，因此它是新药物的潜在靶点，可以结合它并阻断其功能。我们已经在实验室中生产和纯化了这种病毒酶，现在计划设计、合成和开发第一批治疗登革热病毒感染的药物。我们计划通过检查酶的作用，确定其三维结构，并使用计算机和化学方法来获得非常强大的酶作用阻断剂。这些候选药物将针对酶、病毒感染细胞和大鼠进行测试，以确定它们是否可以通过口服或注射给药，以及它们是否有任何毒副作用。该项目将提供有关如何开发药物以阻止登革热及其相关疾病的宝贵信息。

Dengue viruses are carried by mosquitoes and infect millions of people around the world, particularly in tropical countries of SE Asia, Central and South America, Africa and recently in Australia (North Queensland and NT). There is no vaccine or drug available for preventing or treating the infections, which are characterised by severe illness that involves inflammation and fevers that can sometimes be fatal. This proposal focuses on a virus specific enzyme. This enzyme (called a protease) is essential for the virus to multiply and so it is a potential target for new drugs that can bind to it and block its function. We have produced and purified this viral enzyme in the laboratory and now propose to design, synthesize, and develop the first drugs for the treatment of humans infected with dengue virus. We plan to do this by examining the action of the enzyme, determining its three dimensional structure, and using computers and chemical methods to obtain very powerful blockers of enzyme action. These drug candidates will be tested against the enzyme, against cells infected with virus, and in rats to find out if they can be administered by mouth or by injection and if they have any toxic side effects. This project will provide valuable information about how to develop drugs to stop dengue fever and its associated illnesses.