Betulinic acid derivatives as anti-HIV agents

描述（由申请人提供）：尽管高效抗逆转录病毒治疗在控制HIV-1阳性个体中的病毒复制方面取得了成功，但耐药性和副作用等问题往往会损害抗HIV- 1药物的有效性。因此，需要具有新的作用机制的新的抗HIV剂。在努力确定新的抗HIV-1药物，我们已经开发了有效的白桦酸（BA）衍生物，抑制HIV-1的成熟。与目前用于艾滋病治疗的药物相比，这些化合物在结构和机制上是新颖的。目前正在临床前或临床研究的不同阶段评估它们治疗艾滋病的潜力。在抗HIV-1BA衍生物中，贝韦瑞麦处于药物开发的最先进阶段.虽然贝韦瑞是一种有效的HIV-1成熟抑制剂，但II期临床试验结果表明，它对一部分HIV-1阳性个体（30-40%）的有效性较低。因此，能够克服这种高基线耐药性的贝韦瑞类似物有望被开发成抗HIV-1药物。本研究的目的是合成克服高基线耐药性的贝韦瑞类似物。我们先前已经鉴定了C3侧链作为贝韦瑞的抗HIV-1成熟药效团。我们假设，适当的修饰的药效团将创建一类新的bevirimat类似物，是有效的抗耐药病毒。我们计划验证这一假设，并完成本研究的目标，具体目标如下：（1）合成具有优化药效团的BA衍生物。(2)寻找新的萜类化合物骨架和辅助基团，用于合成新的抗病毒成熟抑制剂。(3)确定抗HIV-1成熟BA衍生物的药物结合位点和作用机制。除了对贝韦瑞的高基线耐药性外，临床试验的结果也很有希望。这项研究有望克服这种耐药性，因此，将对开发一类用于艾滋病治疗的新型抗HIV-1成熟抑制剂产生重大影响。 公共卫生相关性：该研究的目的是开发有效的抗HIV-1药物，可以克服与HIV-1成熟抑制剂bevirimat相关的耐药性。除了对贝韦瑞的高基线耐药性外，临床试验的结果非常成功。这项研究有望克服这种耐药性，因此，将对开发用于艾滋病治疗的抗HIV-1成熟抑制剂产生重大影响。

DESCRIPTION (provided by applicant): Despite the success of highly active anti-retroviral therapy in controlling virus replication in HIV-1 positive individuals, problems such as drug resistance and side effects often compromise the effectiveness of anti-HIV- 1 drug. Therefore, new anti-HIV agents with novel mechanisms of action are needed. In an effort to identify novel anti-HIV-1 agents, we have developed potent betulinic acid (BA) derivatives that inhibit HIV-1 maturation. These compounds are structurally and mechanistically novel when compared to the drugs currently used for AIDS therapy. Their potentials for treatment of AIDS are currently being evaluated under different stages of preclinical or clinical studies. Bevirimat is at the most advanced stage of drug development among the anti- HIV-1 BA derivatives. Although bevirimat is a potent HIV-1 maturation inhibitor, results of phase II clinical trials indicate that it is less effective in a subset (30-40%) of HIV-1 positive individuals. Therefore, bevirimat analogs that can overcome this high baseline drug resistance are expected to have great potential to be developed into anti-HIV-1 drugs. The objective of this study is to synthesize bevirimat analogs that overcome the high baseline drug resistance. We have previously identified the C3 side chain as the anti-HIV-1 maturation pharmacophore of bevirimat. We hypothesize that suitable modifications of the pharmacophore will create a new class of bevirimat analogs that are effective against the drug resistant viruses. We plan to test this hypothesis and accomplish the objective of this study with the following Specific Aims: (1) to synthesize BA derivatives with optimized pharmacophores. (2) To identify new terpenoid scaffolds and auxiliary groups for the synthesis of new anti-maturation inhibitors against the drug resistant viruses. (3) To determine the drug binding site and mechanism of action of the anti-HIV-1 maturation BA derivatives. Aside from the high baseline drug resistance to bevirimat, results from clinical trials have been promising. The proposed study is expected to overcome this drug resistance and, as a result, will have a high impact on developing a class of novel anti-HIV-1 maturation inhibitors for AIDS therapy. PUBLIC HEALTH RELEVANCE: The goal of the proposed study is to develop potent anti-HIV-1 agents that can overcome the drug resistance associated with the HIV-1 maturation inhibitor bevirimat. Aside from the high baseline drug resistance to bevirimat, results of clinical trials have been very successful. The proposed study is expected to overcome this drug resistance and, as a result, will have high impact on developing anti-HIV-1 maturation inhibitors for AIDS therapy.