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。它是已知的约70种黄病毒之一(例如登革热、黄热病、西尼罗河病毒、昆军病毒、日本脑炎、圣路易斯脑炎、森林脑炎、澳大利亚脑炎和相关的丙型肝炎病毒)，每年感染全球数亿人，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)发生的流行病具有严重症状、严重神经病理和死亡的特点。仅在美国，2002年就有4,156例感染病例和284例死亡病例，2003年有9,122例感染病例和223例死亡病例，自1999年以来，这种蚊子传播的病毒已经在美国各州以及加拿大和墨西哥迅速传播。(http：--www.cdc.gov-ncidod-dvbid-westnile-index.htm).目前还没有可用的治疗方法或疫苗。该项目的重点是一种被称为西尼罗河病毒NS3蛋白酶的酶，它对病毒的复制至关重要。通过在实验室中研究这种酶，我们可以设计出可以阻断其功能的小分子，这些小分子真正有可能成为开发治疗这种病毒感染者的药物的先导。一个先例是HIV-1蛋白酶抑制剂的成功，这是对感染艾滋病毒的人类最有效的治疗方法。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。我们希望为它们的开发产生候选药物和疫苗以及处于西尼罗河病毒研究前沿的新信息。

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.