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: 7995208
• 负责人: KUO-HSIUNG LEE
• 金额: $ 45.15万
• 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/7995208
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Amino Acids; Anti-HIV Agents; Betulinic Acid; Bioavailable; Biological Assay; Biological Factors; Clinical Trials; Collaborations; Data; Development; Dose; Drug Binding Site; Drug Delivery Systems; Drug Design; Fuzeon; Goals; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV Infections; HIV-1; Lead; Modification; Molecular Mechanisms of Action; Mono-S; Names; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Principal Investigator; Protease Inhibitor; RNA-Directed DNA Polymerase; Research; Schedule; Side; Skeleton; Source; Staging; Structure; Testing; Translational Research; Triterpenes; Viral; base; cost; cost effective; crosslink; drug candidate; drug development; drug resistant virus; improved; inhibitor/antagonist; next generation; novel; pre-clinical; programs; public health relevance; small molecule

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，艾滋病的治疗已扩展到包括 26 种药物，其中包括最新的药物 Fuzeon（一种融合抑制剂），以及更长期开发的 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针对 HIV 感染的单一疗法和双疗法只能暂时有效。此外，Fuzeon不能口服，而RTI和PI药物的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机制的新小分子。 在我们发现和开发 Bevirimat（一种改良三萜和一流的 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三萜作为有效的 HIV-1 进入抑制剂。我们假设可以通过现有先导化合物或天然来源的新三萜的结构优化来鉴定药理学特性优于现有先导化合物的新三萜。该项目将作为跨学科合作项目进行，以加强发现新型有效抗艾滋病药物的转化研究。将测试假设并通过以下具体目标来实现目标。 1. 发现可抑制 HIV-1 进入的新天然产物三萜/先导化合物。三萜类化合物的选择将基于其已证实的抗艾滋病毒活性特征。 2. 通过先导化合物优化获得具有增强的抗HIV-1进入活性的下一代三萜。将对桦木酸进行广泛的修饰，以生产最好的抗艾滋病毒进入抑制剂。修饰将集中在 C-28 侧链、C-19 异丙烯基部分和 A 环上。赋予桦木酸最佳抗 HIV 进入活性的结构将应用于修饰从具体目标 1 中描述的研究中确定的有希望的先导化合物。所有天然和修饰的三萜都将进行生物测定，以抑制 HIV 复制和进入。与我们目前的先导化合物相比，具有优异抗 HIV-1 进入活性的化合物将针对一组遗传多样性的 HIV-1 毒株（包括耐药病毒）进行进一步测试。 3.确定作用的分子机制。该目的的目的是确定三萜的药物结合位点。有关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目标病毒分子 (gp120) 交联，并分析药物结合位点涉及的氨基酸残基。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很可能与一家制药公司合作开发并进入临床试验，并可能在以后作为针对病毒进入的新型抗艾滋病毒药物取得成功。 公共健康相关性：基于良好的初步数据和已确定的先导化合物，本研究打算进行广泛的研究，以生产一种可抑制 HIV-1 进入的最佳修饰三萜。该病毒阶段目前仅针对药物Fuzeon，该药物具有非口服给药和成本高的缺点。本研究计划对多种三萜骨架进行结构修饰并研究作用机制，以经济高效的方式开发口服生物可利用的化合物。目的是发现一种最佳化合物，在制药合作伙伴的帮助下，可以将其开发为抗艾滋病临床试验候选药物，并最终作为治疗艾滋病感染患者的新药。