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: 7418742
• 负责人: KUO-HSIUNG LEE
• 金额: $ 46.43万
• 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/7418742
• 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; Class; Clinical Trials; Collaborations; Data; Development; Dose; Drug Binding Site; Drug Delivery Systems; Drug Design; Drug Kinetics; Drug resistance; Exhibits; 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; Public Health; RNA-Directed DNA Polymerase; Range; Research; Research Design; Research Personnel; Schedule; Side; Skeleton; Source; Staging; Structure; Technology; Testing; Toxic effect; Translational Research; Triterpenes; United States Food and Drug Administration; Viral; base; cost; crosslink; drug resistant virus; improved; inhibitor/antagonist; next generation; novel; pre-clinical; 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单药和双药治疗HIV感染的效果只是暂时的。此外，Fuzeon不能口服，RTI和PI联合用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机制的新小分子药物。