Betulinic acid derivatives as anti-HIV agents.

桦木酸衍生物作为抗 HIV 剂。

• 批准号: 7557845
• 负责人: Chin-Ho Chen
• 金额: $ 29.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7557845
• 关键词: AIDS therapy; Adverse effects; Animals; Anti-HIV Agents; Anti-HIV Therapy; Antiviral Agents; Betulinic Acid; Biological Availability; Chin; Clinical; Development; Drug resistance; Effectiveness; Exhibits; Generations; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Highly Active Antiretroviral Therapy; In Vitro; Individual; Lead; Molecular Mechanisms of Action; Pharmaceutical Preparations; Research Personnel; Resistance; Resistance profile; SCID-hu Mice; Testing; Variant; Viral; Virus Replication; Work; drug development; drug resistant virus; gag Gene Products; in vivo; insight; mouse model; mutant; novel; pharmacophore; programs; resistant strain; small molecule; success

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.

高度活跃的抗逆转录病毒疗法可以有效控制HIV-1阳性个体中的病毒复制。 但是，诸如耐药性和副作用之类的问题通常会损害抗HIV-的有效性 1种药物。因此，需要开发具有新型作用机理的新型抗HIV药物。在 我们为鉴定新型抗HIV-1药物的努力，我们已经合成了有效的双功能β-BA（BA） 通过靶向GP120和GAG蛋白来抑制HIV-1进入和成熟的衍生物。虽然 这些小分子在低纳米性浓度下抑制HIV-1，并具有不同的机制 尚未评估其他抗HIV-1药物的作用，此类化合物的临床潜力尚未评估。 该项目的目的是合成和确定有效的双功能抗HIV BA衍生物 进一步的临床发展。这是朝着我们长期目标发展抗HIV-1代理商的一步 艾滋病治疗的新型作用机制。这项研究的中心假设是双重小说 双功能BA衍生物的作用机制将使化合物有效抑制HIV-1 包括已经抗当前抗HIV药物的菌株。另外，动作的双重机制是 可能会减慢突变体对双功能BA衍生物的抗性的出现。我们计划测试这个 假设并以以下特定目的实现了这项研究的目标：1。合成 比当前铅化合物更有效的生物功能BA衍生物。 2。确定 双功能BA衍生物的作用和耐药性谱的分子机制。 3 确定双功能BA衍生物针对HIV-1主要分离株和生物利用度的功效 小动物。此外，双功能BA衍生物对耐药病毒和HIV-1的影响 还将确定SCID-HU小鼠模型中的复制。新颖的作用机理和 抑制两个靶标的能力使双功能的BA衍生物有望进行抗HIV治疗。 拟议的研究的结果有望提供有关此类临床潜力的见解 艾滋病治疗的化合物。