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：虽然目前的抗逆转录病毒疗法 (ART) 在改变全球艾滋病毒流行进程方面非常有效，但仍无法完全根除这种感染。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。抑制整合病毒基因组转录的新型化合物，从而阻止稳定病毒库产生病毒颗粒，呈现出有价值的差异化治疗潜力在艾滋病毒的治疗中。 Tat 是 HIV 基因表达的有效反式激活因子，对于 RNA 聚合酶 II 合成整合病毒基因组的全长转录本至关重要，是治疗 HIV 时备受追捧的转录靶标。创新：二脱氢 Cortistati A (dCA) 是 Cortistatin 类化合物的代表，已显示出作为 Tat 有效抑制剂的巨大潜力。初步数据：dCA 已被证明可以抑制急性 HIV-1 复制，与 ART 联合使用时可产生病毒抑制的累加效应，并且发现对接受 ART 至少病毒抑制患者的 CD4+T 细胞中的潜伏病毒血症有很大影响三年。然而，dCA 已被证明具有偏离目标的活性，影响其在 HIV 治疗中的安全性，包括有效的抗血管生成作用。具体的目的：本提案的目标是设计一种主要的皮质抑素药物，该药物保留了 Tat 抑制素活性，具有药物样特性，并具有理想的安全性和耐受性，包括减少脱靶抗血管生成活性。在具体目标1中，我们将合成100-200种结构不同的皮质抑素类似物，测试它们抑制HIV-1 Tat活性的能力，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抑素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。在具体目标 3 中，具有强大 Tat 抑制作用、较小的抗血管生成活性和足够的体外“药物样”特性的有前景的合成类似物将进行 HIV 抑制研究和机制研究，以确认有前景的类似物的作用机制。这项第一阶段研究将最终产生用于第一阶段研究的临床前候选药物。