Design & Synthesis of Nonpeptide Protease Inhibitors

描述(申请人提供)：获得性免疫缺陷综合症(艾滋病)是医学史上最具破坏性的流行病之一。2009年，联合国艾滋病规划署的报告估计，自1981年艾滋病流行以来，有3500万人感染艾滋病毒和艾滋病，2500万人死亡，1400万儿童成为孤儿。艾滋病的病原体艾滋病毒的发现导致了一些生化目标的确定，以对抗这种毁灭性的疾病。其中，对蛋白水解酶HIV-1蛋白水解酶的治疗抑制成为关键的药物开发目标。随后设计和发现了蛋白酶抑制剂(PI)，并将其引入高效抗逆转录病毒疗法(HAART)，标志着HIV-1感染和艾滋病管理的新纪元的开始。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，由于出现了具有多药耐药性的艾滋病毒-1变种，长期治疗构成了严重的挑战。在那些最初实现了良好的病毒抑制到无法检测到的水平的患者中，大约有40%-50%的患者经历了治疗失败。这些具有抗药性的艾滋病毒毒株可以传播，这增加了未来治疗选择的进一步不确定性。此外，PI还面临一些严重的限制，包括重大毒性、耐受性和坚持复杂的医疗方案。开发对抗药性艾滋病毒有效且副作用最小的新一代PI对未来艾滋病毒/艾滋病的管理至关重要。 我们对抗耐药性的合作研究工作导致了达鲁那韦的开发，该药于2006年6月首次被批准用于抗药性艾滋病毒的治疗，然后在2008年12月获得全面批准用于所有艾滋病毒/艾滋病患者，包括儿科患者。虽然达鲁那韦已经成为对抗艾滋病毒/艾滋病的一线疗法，但作为一种有效的长期治疗选择，它远不是理想的。在本项目期间，我们基于达鲁那韦或其他PI与HIV-1蛋白酶的络合物的X射线晶体结构，设计并合成了多种高效的PI，它们具有显著的抗病毒活性，并对多重耐药的HIV-1毒株具有良好的耐药性。我们还开发了工具和重要的“主干结合”设计概念来对抗耐药性。此外，我们还发现了一些用于优化的小分子非肽结构先导化合物。最近的一种抑制剂GRL-0519对一组多药耐药的HIV-1变种的效力一直比达鲁那韦提高10倍。该等电点还表现出比HIV-1蛋白酶高10倍的二聚化抑制特性。我们目前建议的研究集中在临床开发的下一代PI的设计、合成和评估上。我们的多学科研究工作包括基于结构的设计、合成、蛋白质-配体X射线结晶学、抑制动力学、分子建模以及深入的病毒和细胞生物学研究。

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.