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: 7917025
• 负责人: KUO-HSIUNG LEE
• 金额: $ 11.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-02-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917025
• 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）：多年来的艾滋病治疗不断扩大，包括26种药物，包括最新的融合抑制剂，除了较长的发达的HIV逆转录酶和蛋白酶抑制剂（RTI和PI分别）。然而，耐药性病毒菌株的快速发展使HIV感染的单疗法和双疗法仅暂时有效。此外，不能口服fuzeon，并且组合RTI和PI药物的给药需要复杂的剂量时间表，这很难维持，并且非常昂贵。因此，仍然需要继续努力发现新的抗HIV药物，特别是对于具有新型抗HIV机制的新小分子。 在我们发现和开发Bevirimat的过程中，修改后的三萜和第一类的HIV成熟抑制剂，我们还发现，适当取代的三萜显示出有效的HIV进入抑制。因此，这项研究的总体目标是进一步研究将三萜的修饰为有效的HIV-1进入抑制剂。我们假设可以通过从天然来源的当前铅或新三萜的结构优化来鉴定具有优于当前铅的药理学特征的新三萜。该项目将作为协作跨学科的努力进行，以增强转化研究，以发现新型有效的抗艾滋病药物。该假设将进行检验，目标将通过以下特定目的实现。 1。发现可以抑制HIV-1进入的新的天然产品衍生的三萜/铅。三萜的选择将基于它们所证明的抗HIV活性谱。 2。通过铅优化获得具有改进的抗HIV-1进入活动的下一代三萜。将进行广泛的β酸修饰，以产生最佳的抗HIV进入抑制剂。修饰将集中于C-28侧链，C-19异丙烯基部分和RING-A。从特定目标1中描述的研究中确定的有前途的铅的修饰，赋予最佳的抗HIV进入活性的结构将应用于所有天然和改良的三萜，以抑制其抑制HIV的复制和进入。具有优质抗HIV-1进入活性的化合物对我们当前的潜在客户将进一步测试，以包括遗传多样的HIV-1菌株，包括抗药性病毒。 3。确定作用的分子机理。此目的的目的是识别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，包括对化合物的结构优化以及与其他抗HIV-1药物的潜在组合。我们实现此目标的方法是将活性三萜交叉与靶病毒分子（GP120）并分析涉及药物结合位点的氨基酸残基。有了良好的初步数据，很可能会发现新颖的有希望的化合物。很可能可以与制药公司合作开发从该项目产生的临床前药物候选者，以进入临床试验，并可能在后来成功成为针对病毒进入的新型抗HIV药物。 公共卫生相关性：基于良好的初步数据和已确定的铅化合物，该研究旨在一项广泛的研究，以产生最佳的修饰三萜，以抑制HIV-1的进入。该病毒阶段目前仅由该药物Fuzeon作为目标，该药物的缺点是非口号和高成本。在本研究中计划了多个三萜骨架的结构修饰和作用研究机理，以以具有成本效益的方式开发口服可生物利用化合物。目的是发现一种最佳化合物，该化合物在药品伙伴的帮助下可以作为抗AIDS临床试验候选者开发，并最终作为治疗受AIDS感染的患者的新药。