Modified Triterpines as Potent HIV Fusion Inhibitors

修饰的三萜类化合物作为有效的 HIV 融合抑制剂

• 批准号: 7535010
• 负责人: KUO-HSIUNG LEE
• 金额: $ 44.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535010
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Adverse effects; Amino Acids; Anti-HIV Agents; Anti-Retroviral Agents; Betulinic Acid; Bioavailable; Biological Assay; Biological Factors; Chemicals; Clinical Trials; Collaborations; Data; Development; Dose; Drug Binding Site; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug resistance; Exhibits; FDA approved; Fuzeon; Goals; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Laboratories; Laboratory Research; Lead; Legal patent; Literature; Methods; Modification; Molecular Mechanisms of Action; Mono-S; Oral Administration; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Protease Inhibitor; RNA-Directed DNA Polymerase; Research; Research Design; Research Personnel; Schedule; Side; Skeleton; Source; Staging; Structure; Technology; Testing; Toxic effect; Translational Research; Triterpenes; Viral; base; cost; crosslink; drug candidate; drug resistant virus; improved; inhibitor/antagonist; next generation; novel; pre-clinical; public health relevance; scaffold; small molecule; subcutaneous; synthetic peptide

DESCRIPTION (provided by applicant): The therapy of AIDS has expanded over the years to include 26 drugs, including the latest drug Fuzeon, a fusion inhibitor, in addition to the longer developed HIV reverse transcriptase and protease inhibitor agents (RTI and PI, respectively). However, rapid development of drug resistant viral strains makes mono- and bi- therapy for HIV infection only transiently effective. In addition, Fuzeon cannot be used orally, and the administration of combination RTI and PI drugs requires complicated dosing schedules, which are hard to maintain, and is quite costly. Therefore, continued effort for the discovery of new anti-HIV drugs, especially for new small molecules with novel anti-HIV mechanisms, is still needed. In the course of our discovery and development of Bevirimat, a modified triterpene and the first-in-class HIV maturation inhibitor, we have also discovered that appropriately substituted triterpenes show potent HIV entry inhibition. Thus, the overall goal of this research is to further study modified triterpenes as potent HIV-1 entry inhibitors. We hypothesize that new triterpenes with a pharmacological profile superior to current leads can be identified through structural optimization of current leads or new triterpenes from natural sources. This project will be carried out as a collaborative interdisciplinary effort to enhance the translational research for discovering novel potent anti-AIDS drugs. The hypothesis will be tested and the goal will be achieved through the following specific aims. 1. To discover new natural product-derived triterpenes/leads that can inhibit HIV-1 entry. Selection of triterpenes will be based upon their demonstrated anti-HIV activity profiles. 2. To obtain a next generation of triterpenes with improved anti-HIV-1 entry activity through lead optimization. Extensive modification of betulinic acid will be performed to produce the best anti-HIV entry inhibitors. The modification will focus on the C-28 side chain, C-19 isopropenyl moiety, and ring-A. The structures conferring the best anti-HIV entry activity for betulinic acid will be applied to the modification of promising leads identified from the studies described in Specific Aim 1. All natural and modified triterpenes will be bioassayed for their inhibition of HIV replication and entry. The compounds with superior anti-HIV-1 entry activity to our current leads will be further tested against a panel of genetically diverse HIV-1 strains, including drug-resistant viruses. 3. To determine the molecular mechanism of action. The objective of this aim is to identify the drug binding site of the triterpenes. Information about the drug binding site is critical for further drug design and development, including structural optimization of the compounds and potential combination with other anti-HIV-1 drugs. Our approach to achieve this aim is to cross-link the active triterpenes to the target viral molecules (gp120) and analyze the amino acid residues that are involved in the drug binding site. With good preliminary data, it is very likely that novel promising compounds will be discovered. It is highly probable that the pre-clinical drug candidates generated from this project can be developed in collaboration with a pharmaceutical company to enter clinical trials, and possibly succeed later on as new anti-HIV drugs targeting viral entry. PUBLIC HEALTH RELEVANCE: Based on good preliminary data and an identified lead compound, this research intends an extensive study to produce an optimal modified triterpene that will inhibit HIV-1 entry. This viral stage is currently targeted only by the drug, Fuzeon, which has drawbacks of non-oral administration and high cost. Structural modification of multiple triterpene skeletons and mechanism of action studies are planned in this study to develop an orally bioavailable compound in a cost-effective manner. The aim is to discover an optimal compound that, with the help of a pharmaceutical partner, can be developed as an anti- AIDS clinical trial candidate and, ultimately, as a new drug to treat AIDS-infected patients.

描述（由申请人提供）：多年来，艾滋病的治疗已经扩展到包括26种药物，包括最新的药物Fuzeon，一种融合抑制剂，以及开发时间较长的HIV逆转录酶和蛋白酶抑制剂（分别为RTI和PI）。然而，耐药病毒株的快速发展使得HIV感染的单药和双药治疗仅短暂有效。此外，Fuzeon不能口服，RTI和PI药物联合给药需要复杂的给药方案，难以维持，而且成本相当高。因此，仍然需要继续努力发现新的抗HIV药物，特别是具有新的抗HIV机制的新的小分子。 在我们发现和开发Bevirimat（一种修饰的三萜和一类HIV成熟抑制剂）的过程中，我们还发现适当取代的三萜显示出有效的HIV进入抑制作用。因此，本研究的总体目标是进一步研究修饰的三萜作为有效的HIV-1进入抑制剂。我们假设，新的三萜类化合物的药理学特征上级目前的铅，可以确定通过结构优化目前的铅或新的三萜类化合物从天然来源。该项目将作为一个跨学科的合作努力，以加强发现新的有效的抗艾滋病药物的转化研究。将通过以下具体目标检验这一假设并实现这一目标。 1.发现新的天然产物衍生的三萜/先导化合物，可以抑制HIV-1进入。三萜类的选择将基于其已证实的抗HIV活性特征。2.通过先导化合物优化获得具有改善的抗HIV-1进入活性的下一代三萜。桦木酸的广泛修饰将被进行以产生最好的抗HIV进入抑制剂。修饰将集中在C-28侧链、C-19异丙烯基部分和环A上。赋予桦木酸最佳抗HIV进入活性的结构将用于修饰从特定目标1中描述的研究中鉴定的有希望的先导化合物。将对所有天然和修饰的三萜类进行生物测定，以确定其对HIV复制和进入的抑制作用。与我们目前的领先药物相比，具有上级抗HIV-1进入活性的化合物将针对一组遗传多样性HIV-1菌株（包括耐药病毒）进行进一步测试。3.以确定作用的分子机制。目的是确定三萜类化合物的药物结合位点。关于药物结合位点的信息对于进一步的药物设计和开发至关重要，包括化合物的结构优化以及与其他抗HIV-1药物的潜在组合。我们实现这一目标的方法是将活性三萜与靶病毒分子（gp 120）交联，并分析参与药物结合位点的氨基酸残基。有了良好的初步数据，很可能会发现新的有前途的化合物。该项目产生的临床前候选药物极有可能与制药公司合作开发，进入临床试验，并可能在以后成功成为针对病毒进入的新的抗艾滋病毒药物。 公共卫生相关性：基于良好的初步数据和确定的先导化合物，本研究打算进行广泛的研究，以产生最佳的修饰三萜，将抑制HIV-1的进入。这种病毒阶段目前仅由药物Fuzeon靶向，其具有非口服给药和高成本的缺点。本研究计划对多个三萜骨架进行结构修饰并进行作用机制研究，以经济有效的方式开发口服生物利用度化合物。目的是发现一种最佳化合物，在制药合作伙伴的帮助下，可以开发为抗艾滋病临床试验候选药物，并最终成为治疗艾滋病感染患者的新药。