Development of SMAC mimetics as latency-reversing agents

 描述(由申请人提供)：对感染艾滋病毒的患者进行联合抗逆转录病毒治疗可以将病毒载量降低到极低水平。然而，停止这些治疗会在几周内导致病毒血症，因为潜伏感染的细胞会持续存在。与其继续让患者接受终生的抗逆转录病毒治疗，不如开发出可以清除潜伏的病毒库的治疗方法，从而允许患者停止所有药物治疗。许多团体都在积极追求这一目标。这一领域临床上最先进的方法之一是组蛋白去乙酰酶抑制剂(HDACi)的使用。在接受抗逆转录病毒治疗的HIV感染者的临床试验中，单剂HDACi治疗后，T细胞中HIV RNA的产量迅速增加，但没有观察到病毒产量的增加。因此，这一单一干预措施对潜在储集层的总体影响尚不清楚。我们最近发现，CIAP1拮抗剂是一类已知的非典型NF-κB信号通路的激活因子，它也可以激活实验细胞系中的潜伏HIV。此外，这些化合物与HDACi协同作用，重新激活潜伏的艾滋病毒。这项提议旨在跟进这些发现，并为临床重新激活艾滋病毒提供化合物，以便能够彻底治愈这些患者的感染。具体地说，我们将进行体外研究，以确定最佳组合 在细胞系模型和患者细胞中对临床期SMAC模拟物和HDACi的研究。此外，还将进行吸收、代谢和毒性的体外分析，并检查药物与药物相互作用的可能性。我们将提高下一代Smac模拟物的效力、疗效和药代动力学特征，并减少它可能存在的任何潜在风险。Smac模拟物和HDACi的优化组合将在HIV潜伏期重新激活的小鼠模型中进行测试，并将确定这种重新激活所涉及的确切机制。

 DESCRIPTION (provided by applicant): Combination antiretroviral therapy for patients infected with HIV can reduce viral loads to extremely low levels. However, cessation of these therapies leads to viremia within weeks due to a persistent reservoir of latently infected cells. Instead of continuing to subject patients to a lifetime of antiretroviral therapy, it would be preferable to develop therapies that could purge the latent viral reservoir, thereby allowing patients to stop all medications. Many groups are actively pursuing this goal. Among the most clinically advanced approaches in this area is the use of histone deacetylase inhibitors (HDACi). In clinical trials where HIV infected patients on ART were treated with a single dose of an HDACi, HIV RNA production in T cells rapidly increased, but no increase in virus production was observed. The overall effect of this single intervention on the latent reservoir is therefore not known. We have recently discovered that cIAP1 antagonists, a class of Smac mimetics that are known activators of the non-canonical NF-κB signaling pathway, can also activate latent HIV in an experimental cell line. Furthermore, these compounds act synergistically with HDACi to reactivate latent HIV. This proposal is designed to follow up on these discoveries and to provide compounds for clinical reactivation of HIV in order to enable a complete cure of infection in these patients. Specifically, we will perform in vitro studies to identify the optimal combinations of clinical-stage Smac mimetics and HDACi in both a cell line model and in patient cells. In addition, in vitro analysis of absorption, metabolism and toxicity with be performed, and the potential for drug-drug interactions will be examined. We will improve the potency, efficacy and pharmacokinetic profile of a next-generation Smac mimetic and reduce any potential liabilities it may have. Optimized combinations of SMac mimetics and HDACi will be tested in a mouse model of HIV latency reactivation and the precise mechanisms involved in this reactivation will be identified.