Betulinic acid derivatives as anti-HIV agents.

描述(申请人提供)：高效抗逆转录病毒疗法可有效控制HIV-1阳性患者的病毒复制。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，需要开发具有新作用机制的新型抗HIV药物。为了确定新的抗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分子浓度下抑制HIV-1，并具有不同于其他抗HIV-1药物的作用机制，但这类化合物的临床潜力尚未得到评估。本项目的目标是合成和鉴定有效的双功能抗HIV BA衍生物，为进一步的临床开发提供依据。这是朝着我们开发具有艾滋病治疗新作用机制的抗HIV-1药物的长期目标迈出的一步。这项研究的中心假设是，双功能BA衍生物的双重新颖作用机制将使化合物能够有效地抑制HIV-1，包括已经对当前抗HIV药物产生抗药性的菌株。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。我们计划验证这一假说，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及耐药谱。3.测定双官能团BA衍生物对HIV-1初级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衍生物在SCID-Hu小鼠模型中对耐药病毒和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衍生物有望成为抗HIV治疗的候选药物。这项拟议的研究结果有望为这类化合物用于艾滋病治疗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.