Design & Synthesis of Nonpeptide Protease Inhibitors

描述（由申请人提供）：获得性免疫缺陷综合征（AIDS）是医学史上最具破坏性的流行病之一。2009年，艾滋病规划署的报告估计，自1981年艾滋病开始流行以来，有3 500万人感染了人类免疫缺陷病毒（艾滋病毒）和艾滋病，2 500万人死亡，1 400万儿童成为孤儿。艾滋病的病原HIV的发现，导致了许多对抗这种毁灭性疾病的生化靶点的确定。其中，治疗性抑制一种蛋白水解酶，HIV-1蛋白酶，成为一个关键的药物开发靶点。随后，蛋白酶抑制剂（pi）的设计和发现，以及它们在高活性抗逆转录病毒疗法（HAART）中的应用，标志着HIV-1感染和艾滋病管理新时代的开始。HAART显著改善了患者的生活质量和预期寿命。目前还没有治愈艾滋病毒/艾滋病的方法，由于出现了多药耐药的艾滋病毒-1变体，长期治疗构成了严峻的挑战。在最初将病毒抑制到无法检测水平的患者中，约有40-50%的患者经历了治疗失败。这些耐药艾滋病毒毒株可以传播，进一步增加了未来治疗方案的不确定性。此外，pi还面临许多严重的限制，包括主要毒性、耐受性和对复杂医疗方案的依从性。开发新一代可有效抵抗耐药艾滋病毒且副作用最小的药物对今后管理艾滋病毒/艾滋病至关重要。

DESCRIPTION (provided by applicant): Acquired immunodeficiency syndrome (AIDS) is one of the most destructive epidemics in medical history. In 2009, the UNAIDS report estimated that 35 million people are living with human immunodeficiency virus (HIV) infection and AIDS, 25 million deaths have occurred, and 14 million children have been orphaned since the epidemic began in 1981. The discovery of HIV, the etiological agent for AIDS, led to the identification of a number of biochemical targets to combat this devastating disease. Among them, therapeutic inhibition of a proteolytic enzyme, HIV-1 protease, emerged as a critical drug-development target. Subsequent design and discovery of protease inhibitors (PIs) and their introduction into the highly active antiretroviral therapy (HAART), marked the beginning of a new era of management of HIV-1 infection and AIDS. HAART significantly improved the quality of life and life expectancy of patients. There is no cure for HIV/AIDS and long-term treatment has posed a serious challenge because of the emergence of multidrug-resistant HIV-1 variants. About 40-50% of those patients who initially achieved favorable viral suppression to undetectable levels experienced treatment failure. These drug-resistant HIV strains can be transmitted, raising further uncertainty with respect to future treatment options. In addition, PIs are faced with a number of serious limitations including, major toxicity, tolerance, and adherence to complex medical regimens. The development of a new generation of PIs effective against drug-resistant HIV and with minimum side effects, are vital to the future management of HIV/AIDS. Our collaborative research efforts to combat drug resistance, led to the development of darunavir which was first approved for treatment against drug-resistant HIV in June, 2006, and then received full approval for all HIV/AIDS patients including pediatric patients in December, 2008. While darunavir has become a front line therapy against HIV/AIDS, it is far from ideal as an effective long-term treatment option. During this project period, based upon X-ray crystal structures of complexes of darunavir or other PIs with HIV-1 protease, we designed and synthesized a diverse class of potent PIs with marked antiviral activity, and excellent drug-resistance profiles against multidrug-resistant HIV-1 strains. We have also developed tools and important 'backbone binding' design concepts to combat drug-resistance. Furthermore, we have discovered a number of small molecule nonpeptide structural leads for optimization. A recent inhibitor, GRL-0519, has consistently shown a 10-fold improvement of potency compared to darunavir against a panel of multidrug-resistant HIV-1 variants. This PI also exhibited 10-fold better dimerization inhibitory properties of HIV-1 protease. Our current proposed studies are now focused on design, synthesis, and evaluation of the next generation of PIs for clinical development. Our multidisciplinary research efforts integrate structure-based design, synthesis, protein-ligand X-ray crystallography, inhibition kinetics, molecular modeling, and in-depth virus and cell-biological studies. PUBLIC HEALTH RELEVANCE: The 2010 UNAIDS reports 35 million people are living with HIV/AIDS (Acquired Immunodeficiency Syndrome). Progress against this global pandemic requires innovative improved treatment. This proposal details our design and synthesis of next generation protease inhibitors to address critical problems of existing therapy.