The West Nile viral protease, NS3: a target for antiviral drug and vaccine design

西尼罗河病毒（WNV）于1937年首次从乌干达西尼罗河地区的一名妇女身上分离出来。它是约70种已知黄病毒之一（如登革热、黄热病、西尼罗河病毒、昆仑病毒、日本脑炎、圣路易斯脑炎、蜱传脑炎、澳大利亚脑炎和相关的丙型肝炎病毒），每年感染全世界数亿人，特别是在热带和亚热带地区，并造成重大公共卫生问题。西尼罗河病毒在中东、非洲部分地区和欧洲流行，但最近在以色列（1998年）、罗马尼亚（1996年）、美国（1999年）和英国（2003年）流行的特点是严重的症状、严重的神经病理学和死亡。仅在美国，2002年就有4 156人感染，284人死亡，2003年有9122人感染，223人死亡，这种蚊子传播的病毒自1999年以来迅速蔓延到美国所有州，并进入加拿大和墨西哥（网址：www.cdc.gov-ncidod-dvbid-westnile-index.htm）。没有治疗方法或疫苗可用。这个项目的重点是一种酶，即西尼罗病毒NS3蛋白酶，它对病毒的复制至关重要。通过在实验室研究这种酶，我们可以设计出能够阻断其功能的小分子，这些小分子具有开发针对这种病毒感染者的药物治疗的真正潜力。HIV-1蛋白酶抑制剂的成功是一个先例，它是治疗hiv感染者最有效的方法。我们的研究还将用于开发潜在的疫苗。这门科学涉及蛋白酶、药物设计和开发、病毒学（包括西尼罗河病毒学）和疫苗开发方面的专家。我们期望在西尼罗病毒研究的前沿产生药物和候选疫苗，并为其开发提供新的信息。

The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003) have been characterized by severe symptoms , severe neurological pathology, and fatalities. In the USA alone there were 4,156 infections and 284 deaths in 2002, 9122 infections and 223 deaths in 2003, and this mosquito borne virus has quickly spread since 1999 through all USA states and into Canada and Mexico (http:--www.cdc.gov-ncidod-dvbid-westnile-index.htm). No treatments or vaccines are available. This project focuses on an enzyme, known as the West Nile Virus NS3 protease, that is essential for replication of the virus. By studying the enzyme in the laboratory we can design small molecules that can block its function and these have real potential as leads for development of drug treatments for people infected by this virus. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections. Our studies will also be used to develop potential vaccines. The science involves experts on protease enzymes, drug design and development, virology including West Nile virology, and vaccine development. We expect to generate drug and vaccine candidates and new information for their development that is at the cutting edge of West Nile Virus research.