Development of DSB, a novel potent HIV inhibitor

DSB 的开发，一种新型有效的 HIV 抑制剂

• 批准号: 6762391
• 负责人: GRAHAM P ALLAWAY
• 金额: $ 84万
• 依托单位: PANACOS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6762391
• 关键词: HIV infections; SCID mouse; antiAIDS agent; antiviral agents; clinical research; clinical trial phase I; dogs; drug design /synthesis /production; drug metabolism; human immunodeficiency virus; human subject; laboratory rat; liver cells; microsomes; patient oriented research; pharmacokinetics; plant extracts; terpenes; HIV infections; SCID mouse; antiAIDS agent; antiviral agents; clinical research; clinical trial phase I; dogs; drug design /synthesis /production; drug metabolism; human immunodeficiency virus; human subject; laboratory rat; liver cells; microsomes; patient oriented research; pharmacokinetics; plant extracts; terpenes

Description (provided by applicant): There is a pressing need for new drugs to treat HIV infection by virus strains that are resistant to the approved reverse transcriptase and protease inhibitors. Panacos Pharmaceuticals' approach to overcoming drug resistance involves identifying HIV drug candidates with novel mechanisms of action. In collaboration with Professor K.H. Lee of The University of North Carolina at Chapel Hill, Panacos has identified a promising HIV inhibitor, dimethyl succinyl betulinic acid (DSB). DSB potently inhibits HIV replication in vitro and is orally available in rats with a half-life of several hours. During the past few months, new data have been generated on DSB that provide a compelling case for the continued development of this compound. Of particular importance, it has been shown that DSB is the first in a new class of HIV drug candidates that block the last stage in the virus life cycle: budding/maturation. Furthermore, in vitro assays have demonstrated that DSB retains its nanomolar inhibitory activity against drug resistant strains of HIV, including isolates resistant to the three classes of approved drugs. This Phase II SBIR proposal has two major goals: First to identify DSB's molecular target. Mechanism of action studies will focus on targets that have been shown to play a role in HIV budding/maturation and will include determining the effect of DSB on: gag processing (p24-p2 cleavage); interaction between TSG 101 and the gag L domain; RNA dimerization; and cyclophilin incorporation into virions. The second goal is to complete pre-clinical testing of DSB, file an IND and initiate clinical testing of the novel drug candidate, focusing on the study of pharmacokinetics and safety in uninfected volunteers. If the results of pre-clinical testing indicate that DSB does not have suitable properties for clinical development, it will be replaced by a suitable analog generated during the project. The results of initial clinical studies in normal volunteers will be used as the basis to plan and perform efficacy studies in HIV-infected individuals that will be carried out subsequent to the Phase II grant period.

描述（由申请人提供）： 迫切需要新药治疗对抗认可的逆转录酶和蛋白酶抑制剂的病毒菌株的HIV感染。 Panacos Pharmaceuticals克服耐药性的方法涉及通过新型作用机理鉴定HIV候选药物。与K.H.教授合作Panacos北卡罗来纳大学教堂山的Lee已确定了有前途的HIV抑制剂二甲基琥珀酰β-苯丁基酸（DSB）。 DSB在体外有效抑制艾滋病毒复制，并在半衰期为几个小时的大鼠中口服。在过去的几个月中，在DSB上生成了新数据，为这种化合物的持续开发提供了令人信服的案例。特别重要的是，已经表明，DSB是一类新的HIV药物候选者中的第一个阻止病毒生命周期的最后阶段：萌芽/成熟。此外，体外测定表明，DSB保留其对HIV耐药性HIV抗药性菌株的纳摩尔抑制活性，包括对三类批准药物的抗性分离株。该II期SBIR提案有两个主要目标：首先确定DSB的分子靶标。作用研究机理将集中于已显示在HIV萌芽/成熟中发挥作用的靶标，并包括确定DSB对：GAG加工（P24-P2裂解）的影响； TSG 101与GAG L结构域之间的相互作用； RNA二聚化；并融入病毒体中。第二个目标是完成DSB的临床前测试，对IND进行启动并开始对新型药物的临床测试，重点研究未感染的志愿者的药代动力学和安全性的研究。如果临床前测试的结果表明DSB没有适合临床发育的特性，则将被项目期间产生的合适的模拟代替。正常志愿者中最初的临床研究结果将被用作计划和执行艾滋病毒感染者的疗效研究的基础，这些基础将在II期赠款期后进行。