Transcriptional silencing of latent HIV infection - a novel small molecule class

产品说明：尽管目前的抗逆转录病毒疗法（ART）在改变全球艾滋病毒流行的过程中非常有效，但未能完全根除感染。这导致了耐药突变株的出现、潜伏性疾病的现象以及与长期治疗相关的许多依从性和毒性问题。抑制整合的病毒基因组的转录，从而防止从稳定的病毒储库产生病毒颗粒的新化合物呈现出有价值的和差异化的治疗潜力 艾滋病的治疗。达特是HIV基因表达的有效反式激活因子，对于通过RNA聚合酶II合成整合的病毒基因组的全长转录物是必需的，是治疗HIV的高度寻求的转录靶。创新：二脱氢皮质抑素A（dCA）是皮质抑素类化合物的代表，已证明其作为达特的有效抑制剂的显著潜力。初步数据：dCA已被证明可抑制急性HIV-1复制，与ART联合使用时已证明具有病毒抑制的累加效应，并且已发现对接受ART治疗至少3年的病毒抑制患者的CD 4 +T细胞中的潜伏病毒血症具有高度影响。然而，dCA已被证明具有脱靶活性，影响其在HIV治疗中的安全性，包括强效抗血管生成作用。具体 目的：该提案的目标是设计一种皮质抑素先导剂，其保留达特抑制素活性，具有药物样性质，并且具有期望的安全性和耐受性特征，包括脱靶抗血管生成活性的降低。在具体目标1中，我们将合成100-200个结构不同的皮质抑素类似物，测试它们抑制HIV-1达特活性的能力，并在未感染的HeLa CD 4细胞中进行细胞毒性测定。在研究目标2中，我们将表征铅样皮质抑素类似物的抗血管生成活性和“药物样”性质，包括溶解度、人血浆蛋白结合、肝微粒体稳定性和抗血管生成蛋白450抑制。在特定目标3中，显示出有效的达特抑制、微小的抗血管生成活性和足够的体外“药物样”性质的有希望的合成类似物将进行HIV抑制研究和机制研究，以确认有希望的类似物的作用机制。本I期研究将最终产生用于I期研究的临床前候选药物。

DESCRIPTION: Though highly effective in changing the course of the global HIV epidemic, current Antiretroviral Therapy (ART) fails to eradicate the infection completely. This has led to the emergence of drug-resistant mutant strains, the phenomenon of latent disease and a number of adherence and toxicity issues associate with long-term therapy. Novel compounds that inhibit transcription from integrated viral genomes, thereby preventing the production of vira particles from stable viral reservoirs, present a valuable and differentiated therapeutic potential in the treatment of HIV. Tat, a potent transactivator of HIV gene expression essential for the synthesis of full-length transcripts of the integrated viral genome by RNA polymerase II, is a highly sought after transcription target for the treatment of HIV. Innovation: Didehydro-cortistati A (dCA), a representative of the cortistatin class of compounds, has demonstrated significant potential as a potent inhibitor of Tat. Preliminary Data: dCA has been shown to inhibit acute HIV-1 replication, has demonstrated additive effect of viral inhibition when combined with ART, and has been found to highly impact latent viremia in CD4+T cells of virally suppressed patients receiving ART for at least three years. However, dCA has been shown to have off target activity that impacts its safety profile in HIV therapy, including potent anti-angiogenesis effect. Specific Aims: The goal of this proposal is the design of a lead cortistatin agent that retains Tat inhibitin activity, has drug-like properties, and has a desirable safety and tolerability profile including te reduction of off-target anti-angiogenesis activity. In Specific Aim 1, we will synthesize 100-200 structurally divergent cortistatin analogs, test them for their ability to inhibit HIV-1 Tat activiy, and conduct cellular toxicity determination in uninfected HeLa CD4 cells. In Study Aim 2, we will characterize lead-like cortistatin analogs for antiangiogenic activity and "drug-like" properties including solubility, human plasma protein binding, liver microsomal stability, and CYP P450 inhibition. In Specific Aim 3, promising synthetic analogs that display potent Tat inhibition, diminutive anti-angiogenesis activity, and adequate in vitro "drug-like" properties will undergo HIV inhibition studies and mechanistic studies to confirm promising analogs' mechanism of action. This Phase I study will culminate in the generation of a pre-clinical candidate for Phase I investigation.