Design & Synthesis of Nonpeptide Protease Inhibitors

描述（由申请人提供）：获得性免疫缺陷综合征（艾滋病）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。艾滋病的病原体艾滋病毒的发现，导致确定了一些生化目标，以打击这一毁灭性的疾病。其中，对蛋白水解酶HIV-1蛋白酶的治疗性抑制成为关键的药物开发目标。随后蛋白酶抑制剂（PI）的设计和发现，以及将其引入高效抗逆转录病毒疗法（HAART），标志着HIV-1感染和艾滋病管理新时代的开始。HAART显著提高了患者的生活质量和预期寿命。艾滋病毒/艾滋病无法治愈，由于出现了耐多药的艾滋病毒1变种，长期治疗构成了严重挑战。最初达到有利的病毒抑制至不可检测水平的患者中约40-50%经历治疗失败。这些耐药的艾滋病毒菌株可以传播，这进一步增加了未来治疗方案的不确定性。此外，PI面临着许多严重的局限性，包括严重的毒性、耐受性和对复杂医疗方案的依从性。开发新一代能有效对抗抗药性艾滋病毒并具有最小副作用的PI，对今后艾滋病毒/艾滋病的管理至关重要。 我们的合作研究努力，以打击耐药性，导致开发的darunavir首次批准用于治疗耐药性艾滋病毒在2006年6月，然后获得全面批准所有艾滋病毒/艾滋病患者，包括儿科患者在2008年12月。虽然达芦那韦已成为对抗艾滋病毒/艾滋病的一线疗法，但作为一种有效的长期治疗选择，它远非理想。在本项目期间，基于地瑞那韦或其他PI与HIV-1蛋白酶的复合物的X-射线晶体结构，我们设计并合成了具有显著抗病毒活性的多种有效PI，并对多药耐药HIV-1菌株具有优异的耐药性。我们还开发了工具和重要的“主干绑定”设计概念，以对抗耐药性。此外，我们还发现了一些小分子非肽结构的优化线索。最近的一种抑制剂GRL-0519，与地瑞那韦相比，对一组多药耐药HIV-1变异体的效力一直显示出10倍的改善。该PI还表现出10倍更好的HIV-1蛋白酶的二聚化抑制特性。我们目前提出的研究现在集中在设计，合成和评价下一代PI的临床开发。我们的多学科研究工作整合了基于结构的设计，合成，蛋白质配体X射线晶体学，抑制动力学，分子建模以及深入的病毒和细胞生物学研究。 公共卫生相关性：2010年联合国艾滋病规划署报告说，有3500万人感染艾滋病毒/艾滋病（获得性免疫缺陷综合症）。要想在防治这一全球流行病方面取得进展，就需要改进治疗方法。该提案详细介绍了我们设计和合成的下一代蛋白酶抑制剂，以解决现有治疗的关键问题。

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.