Betulinic acid derivatives as anti-HIV agents.

描述（由申请人提供）：高效抗逆转录病毒疗法可有效控制HIV-1阳性个体的病毒复制。然而，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，需要开发具有新的作用机制的新的抗HIV剂。为了鉴定新型抗HIV-1药物，我们合成了有效的双功能桦木酸（BA）衍生物，通过靶向gp 120和gag蛋白抑制HIV-1进入和成熟。尽管这些小分子在低纳摩尔浓度下抑制HIV-1，并且具有与其他抗HIV-1药物不同的作用机制，但尚未评估这类化合物的临床潜力。本项目的目标是合成和鉴定有效的双功能抗HIV BA衍生物，以进一步临床开发。这是朝着我们的长期目标迈出的一步，即开发具有新的艾滋病治疗作用机制的抗HIV-1药物。本研究的中心假设是双功能BA衍生物的双重新作用机制将允许化合物有效抑制HIV-1，包括已经对当前抗HIV药物具有抗性的菌株。此外，双重作用机制可能会减缓对双功能BA衍生物的抗性突变体的出现。我们计划验证这一假设，并实现本研究的目标，具体目标如下：1。合成比现有先导化合物更有效的双功能BA衍生物。2.确定双功能BA衍生物的分子作用机制和耐药性特征。3.确定双功能BA衍生物对HIV-1原代分离株的有效性和在小动物中的生物利用度。此外，还将确定双功能BA衍生物对SCID-hu小鼠模型中的耐药病毒和HIV-1复制的影响。新颖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药物。拟议的研究结果预计将提供深入了解这类化合物用于艾滋病治疗的临床潜力。

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.