Betulinic acid derivatives as anti-HIV agents.

高效抗逆转录病毒治疗可以有效地控制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艾滋病毒的有效性， 1毒品因此，需要开发具有新的作用机制的新的抗HIV剂。在 为了寻找新的抗HIV-1药物，我们合成了有效的双功能桦木酸（BA） 通过靶向gp 120和gag蛋白抑制HIV-1进入和成熟的衍生物。虽然 这些小分子在低纳摩尔浓度下抑制HIV-1， 由于其他抗HIV-1药物的作用，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， 进一步临床开发。这是朝着我们开发抗HIV-1药物的长期目标迈出的一步， 艾滋病治疗的新作用机制。本研究的中心假设是， 双官能BA衍生物的作用机制将允许化合物有效地抑制HIV-1 包括已经对目前的抗艾滋病毒药物产生耐药性的菌株。此外，双重作用机制是 可能减缓对双功能BA衍生物具有抗性的突变体的出现。我们计划测试一下 提出假设并实现本研究的目的，具体目标如下：1.合成 双官能BA衍生物，其比目前的先导化合物更有效。2.确定 双功能BA衍生物的分子作用机制和耐药性概况。3.到 测定双功能BA衍生物对HIV-1原代分离株的效力和在 小动物。此外，还研究了双功能BA衍生物对耐药病毒和HIV-1的作用。 还将测定SCID-hu小鼠模型中的复制。新的作用机制和 抑制两个靶点的能力使得双功能BA衍生物成为抗HIV治疗的有希望的候选物。 预计拟议研究的结果将为这类药物的临床潜力提供见解。 用于艾滋病治疗的化合物。

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.