Design and discovery of HIV-1 IN inhibitors with a novel mechanism of action

描述（由申请人提供）：本研究的长期目标是确定新分子作为抑制HIV-1整合酶（IN）和预防HIV-1复制的潜在临床候选分子。据报道，细胞染色质系固LEDGF融合蛋白通过与in的关联在HIV复制中至关重要，使其成为抗病毒治疗的理想靶点。拟议的研究旨在设计基于药物团的模型，以挖掘分子数据库中能够破坏IN-LEDGF复合物形成的新化合物。具体目标I是利用晶体学数据作为平台，设计具有独立于催化位点的新机制的位点特异性IN抑制剂。从IN-LEDGF复合物模型中鉴定出的初始化合物集将提供未来基于活性的模型，以加强对其他先导分子的发现。Specific aim II旨在过滤ADMET模拟中预测的具有良好理化性质的IN和LEDGF拮抗剂亚群，以生成新的Q-SAR模型，旨在识别在体内显示活性的新抑制剂。特异性目的III旨在确定已鉴定的IN抑制剂与已知的抗hiv化合物在体外和基于细胞的测定中联合使用的协同效应。艾滋病是世界上最严重的健康问题之一。2005年，世界卫生组织和美国政府共同努力，增加发展中国家抗逆转录病毒药物的可获得性，因为疾病预防控制中心宣布美国的艾滋病毒感染人数已达到100万。2004年至2006年，北美艾滋病患者人数增加了16.7%，而撒哈拉以南非洲增加了4.7%，东南亚增加了5.6%。据联合国艾滋病毒/艾滋病规划署（UNAIDS）的联合报告，东亚的发病率增加了21%。如果没有有效的抗病毒治疗方案，HIV患者最终会死于HIV-1免疫缺陷。公共卫生相关性：耐药病毒株的出现和世界范围内HIV-1感染的指数增长反映了开发具有新的作用机制的新型HIV-1疗法以纳入HAART药物方案的紧迫性。

DESCRIPTION (provided by applicant): The long term objective of this study is to identify novel molecules as potential clinical candidates for the inhibition of HIV-1 integrase (IN) and the prevention of HIV-1 replication. Cellular chromatin-tethering LEDGF fusion protein was reported to be essential in HIV replication through an association with IN, making it an ideal target for antiviral therapy. The proposed studies aim to design pharmacophore-based models to mine molecular databases for novel compounds that will disrupt IN-LEDGF complex formation. Specific aim I is directed at using crystallography data as a platform to design site-specific IN inhibitors with a novel mechanism independent of catalytic site. Initial sets of compounds identified from IN-LEDGF complex models will provide future activity-based models to enhance discovery for additional lead molecules. Specific aim II is designed to filter subpopulations of IN and LEDGF antagonists with favorable physiochemical properties predicted in ADMET simulations to generate new Q-SAR models that will aim to identify new inhibitors showing activity in vivo. Specific aim III is designed to determine the synergistic effects of identified IN inhibitors in combination with known anti-HIV compounds in vitro and in cell-based assays. AIDS is one of the world's most serious health problems. In 2005, the world health organization and the U.S. government created a joint effort to increase the availability of antiretroviral drugs to developing countries as the CDC announced HIV had reached one million infections in the U.S. Between 2004 and 2006, there was a 16.7 % increase in the number of AIDS patients in North America, compared with a 4.7 % increase in Sub-Saharan Africa, a 5.6 % in South East Asia, and 21 % increase in East Asia as reported by a joint United Nations Program on HIV/AIDS (UNAIDS). Without an effective antiviral regimen HIV subjects will eventually succumb to HIV-1 immunodeficiency. PUBLIC HEALTH RELEVANCE: The emergence of drug resistant viral strains and the exponential increase in HIV-1 infections worldwide echoes an urgency to develop new HIV-1 therapeutics with novel mechanisms of action to incorporate into HAART drug regimes.