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

潜伏 HIV 感染的转录沉默——一类新型小分子

基本信息

批准号：
8731293
负责人：
PHIL S BARAN
金额：
$ 29.19万
依托单位：
SIRENAS MARINE DISCOVERY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731293
关键词：
Acute Adherence Affect Alkaloids Angiogenesis Inhibitors Binding Biological Assay CD4 Positive T Lymphocytes Cell Survival Cells Characteristics Chemicals Combined Modality Therapy Cytochrome P450 Data Derivation procedure Disease Drug resistance EMSA Endothelial Cells Epidemic Exhibits Gene Expression Generations Genetic Transcription Goals HIV HIV-1 Head Hela Cells Human In Vitro Individual Infection Investigation Isoquinolines Lead Length Life Life Cycle Stages Liver Luciferases Marines Medicine Modification Patients Pharmaceutical Preparations Phase Plasma Proteins Porifera Prednisone Production Property Protein Binding Proviruses RNA RNA Polymerase II Recombinants Reporter Safety Solubility Staging Steroids Structure Structure-Activity Relationship Testing Therapeutic Toxic effect Trans-Activators Transcript Umbilical vein Viral Viral Genome Viremia Virus Virus Diseases Virus Latency Virus Replication analog antiangiogenesis therapy antiretroviral therapy base chemical synthesis cortistatin design drug candidate fitness functional group improved inhibitor/antagonist innovation mutant novel particle pharmacophore phase 1 study pre-clinical prevent promoter public health relevance scaffold serum sodium transport inhibitor skeletal small molecule viral RNA

项目摘要

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.

描述：尽管在改变全球HIV流行的过程中非常有效，但目前的抗逆转录病毒疗法（ART）并未完全消除感染。这导致了抗药性突变菌株的出现，潜在疾病的现象以及许多与长期治疗有关的粘附和毒性问题。抑制综合病毒基因组转录的新型化合物，从而防止了稳定病毒储层中的Vira颗粒产生在治疗艾滋病毒中。 TAT是RNA聚合酶II的全长转录本所必需的HIV基因表达的有效反式激活剂，是RNA聚合酶II的全长转录物，是对HIV治疗的备受追捧的转录靶标。创新：Cortistatin类化合物的代表Didehydro-cortistati A（DCA）表现出了作为TAT有效抑制剂的巨大潜力。初步数据：DCA已显示可抑制急性HIV-1复制，与ART结合使用时证明了病毒抑制作用的加性作用，并且发现在接受ART至少三年的病毒抑制患者的CD4+T细胞中高度影响潜在的病毒血症。但是，DCA已被证明具有影响其在HIV疗法中的安全性的目标活动，包括有效的抗血管生成作用。具体的目的：该提案的目的是设计铅皮质蛋白剂，该铅皮质蛋白剂保持TAT抑制素活性，具有类似药物的特性，并且具有理想的安全性和耐受性，包括降低脱靶抗血管生成活性。在特定的目标1中，我们将合成100-200个结构上不同的皮质蛋白类似物，测试它们是否抑制HIV-1 TAT Activiy的能力，并在未感染的HELA CD4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蛋白类似物的抗血管生成活性和“药物样”特性，包括溶解度，人血浆蛋白结合，肝微粒体稳定性和CYP P450抑制作用。在特定的目标3中，有希望的合成类似物表现出有效的TAT抑制作用，少量的抗血管生成活性和足够的体外“药物样”特性，将接受HIV抑制研究和机理研究，以确认有希望的类似物的作用机理。这项I阶段的研究将最终导致I期研究的临床前候选者的产生。