Betulinic acid derivatives as anti-HIV agents.

描述（申请人提供）：高效抗逆转录病毒治疗可有效控制HIV-1阳性个体的病毒复制。然而，诸如耐药性和副作用等问题往往会影响抗hiv -1药物的有效性。因此，需要开发具有新的作用机制的新型抗hiv药物。为了寻找新的抗HIV-1药物，我们合成了有效的双功能白桦酸（BA）衍生物，通过靶向gp120和gag蛋白来抑制HIV-1的进入和成熟。尽管这些小分子在低纳米摩尔浓度下抑制HIV-1，并且具有与其他抗HIV-1药物不同的作用机制，但这类化合物的临床潜力尚未得到评估。该项目的目的是合成和鉴定有效的双功能抗hiv BA衍生物，用于进一步的临床开发。我们的长期目标是开发具有新的艾滋病治疗作用机制的抗hiv -1药物，这是向这一目标迈出的一步。本研究的中心假设是，双功能BA衍生物的双重作用机制将使这些化合物能够有效抑制HIV-1，包括已经对当前抗hiv药物产生耐药性的菌株。此外，双重作用机制可能会减缓对双功能BA衍生物产生抗性的突变体的出现。我们计划对这一假设进行检验，并实现本研究的目标，具体目的如下：1。合成比现有先导化合物更有效的双官能团BA衍生物。2. 确定双功能BA衍生物的分子作用机制和耐药谱。3. 目的：确定双功能BA衍生物对HIV-1原代分离株的药效及在小动物体内的生物利用度。此外，还将确定双功能BA衍生物对耐药病毒和SCID-hu小鼠模型中HIV-1复制的影响。新的作用机制和抑制两个靶点的能力使双功能BA衍生物成为抗hiv治疗的有希望的候选者。该研究的结果有望为这类化合物治疗艾滋病的临床潜力提供见解。

DESCRIPTION (provided by applicant): Highly active anti-retroviral therapy can effectively control virus replication in HIV-1 positive individuals. However, problems such as drug resistance and side effects often compromise the effectiveness of anti-HIV-1 drugs. Therefore, the development of new anti-HIV agents with novel mechanisms of action is needed. In an effort to identify novel anti-HIV-1 agents, we have synthesized potent bi-functional betulinic acid (BA) derivatives that inhibit both HIV-1 entry and maturation by targeting gp120 and gag proteins. Although these small molecules inhibit HIV-1 at low nanomolarity concentrations and have different mechanisms of actions from other anti-HIV-1 drugs, the clinical potential of this class of compounds has not been evaluated. The objective of this project is to synthesize and identify potent bi-functional anti-HIV BA derivatives for further clinical development. This is a step toward our long term goal to develop anti-HIV-1 agents with novel mechanisms of action for AIDS therapy. The central hypothesis of this study is that the dual novel mechanisms of action of the bi-functional BA derivatives will allow the compounds to potently inhibit HIV-1 including strains already resistant to current anti-HIV drugs. In addition, the dual mechanisms of action are likely to slow the emergence of mutants resistant to the bi-functional BA derivatives. We plan to test this hypothesis and accomplish the objective of this study with the following specific aims: 1. To synthesize the bi-functional BA derivatives that are more potent than the current lead compounds. 2. To determine the molecular mechanisms of action and drug resistance profiles of the bi-functional BA derivatives. 3. To determine the efficacy of the bi-functional BA derivatives against HIV-1 primary isolates and bioavailability in small animals. In addition, the effect of the bi-functional BA derivatives on drug resistant viruses and HIV-1 replication in a SCID-hu mouse model will also be determined. The novel mechanisms of action and the ability to inhibit two targets make the bi-functional BA derivatives promising candidates for anti-HIV therapy. Results of the proposed study are expected to provide insights into the clinical potential of this class of compounds for AIDS therapy.