STRUCT-BASED DESIGN OF INHIBITORS FOR FLU NEURAMINIDASE

描述：(改编自申请者摘要)流感是一种严重的 在平均季节造成约10,000至20,000人死亡的疾病。 尽管疫苗已经问世多年，但它们 在人类人口中对流感的控制不力。缺乏 疫苗疗法的有效性是由于病毒对 改变其抗原性结构，逃避宿主的免疫系统。A更多 遏制流感的有效方法可能是通过抗病毒药物 干扰关键的病毒功能。一个明显的目标是酶 负责病毒的传播，神经氨酸酶。 50多年的实证研究没有产生任何有效的结果 抗流感药物。目前在美国被批准用于治疗的唯一药物 预防和治疗流感感染的药物是金刚烷胺 盐酸盐。然而，对金刚烷胺具有抗药性的突变株很容易 与世隔绝。因此，显然需要一种比这更成功的方法 实证研究的方法是。 本提案中所述工作的目标是确定 分子结构，并了解其作用机制 甲型流感神经氨酸酶。长期目标是设计和合成 有效安全的神经氨酸酶活性部位抑制剂 人类人群中对抗流感的抗病毒药物。

DESCRIPTION: (Adapted from Applicant's Abstract) Influenza is a serious disease that causes about 10,000 to 20,000 deaths in an average season. Even though vaccines have been available for a number of years , they poorly control influenza in the human population. The lack of effectiveness of the vaccine therapy is due to the capacity of the virus to change its antigenic structure and escape the host's immune system. A more efficient way to curb influenza may be via anti-viral agents which interfere with crucial viral functions. One obvious target is the enzyme responsible for the spread of the virus, neuraminidase. More than 50 years of empirical research have not produced any effective anti-influenza agents. The only drug currently approved in the U.S. for the prophylaxis and therapy of influenza infection is amantadine hydrochloride. However, mutants resistant to amantadine are readily isolated. Thus, there is a clear need for a more successful approach than the empirical methods have been. The objective of the work described in this proposal is to determine the molecular architecture and understand the mechanism of action of the influenza A neuraminidase. The long-term goal is to design and synthesize active-site inhibitors of neuraminidase which are effective and safe anti-viral agents against influenza in the human population.