Development of SMAC mimetics as latency-reversing agents

 描述（由申请人提供）：HIV感染患者的联合抗逆转录病毒治疗可将病毒载量降至极低水平。然而，由于潜伏感染细胞的持续储存，停止这些治疗会在数周内导致病毒血症。与其让患者终生接受抗逆转录病毒治疗，不如开发出能够清除潜伏病毒库的疗法，从而让患者停止所有药物治疗。许多团体正在积极追求这一目标。在这一领域最先进的临床方法是使用组蛋白脱乙酰酶抑制剂（HDACi）。在接受ART的HIV感染患者接受单剂量HDACi治疗的临床试验中，T细胞中的HIV RNA产量迅速增加，但未观察到病毒产量增加。因此，这种单一干预对潜在储层的总体影响尚不清楚。我们最近发现，cIAP 1拮抗剂，一类Smac模拟物，是已知的非经典NF-κB信号通路的激活剂，也可以激活实验细胞系中的潜伏HIV。此外，这些化合物与HDACi协同作用以重新激活潜伏的HIV。该提案旨在跟进这些发现，并提供用于临床重新激活HIV的化合物，以便能够完全治愈这些患者的感染。具体来说，我们将进行体外研究，以确定最佳组合 临床阶段Smac模拟物和HDACi在细胞系模型和患者细胞中的表达。此外，还将进行吸收、代谢和毒性的体外分析，并检查药物间相互作用的可能性。我们将提高下一代Smac模拟物的效价、功效和药代动力学特征，并减少其可能存在的任何潜在责任。SMac模拟物和HDACi的优化组合将在HIV潜伏期再激活的小鼠模型中进行测试，并将鉴定该再激活中涉及的精确机制。

 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.