Structural analysis and therapeutic nanobody development of KSHV G-protein coupled receptor

KSHV G 蛋白偶联受体的结构分析和治疗性纳米抗体开发

• 批准号: 10413218
• 负责人: Jae U Jung
• 金额: $ 49.09万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413218
• 关键词: 3-Dimensional; AIDS/HIV problem; Agonist; Antibodies; Binding; Biochemical; Biological Assay; CXCL1 gene; Cancer Etiology; Cell surface; Cells; Cessation of life; Chromium; Clinical Trials; Cryoelectron Microscopy; Crystallization; Cyclic AMP; Development; Disease; Disulfides; Drug Targeting; Epithelial; Etiology; FDA approved; G-Protein-Coupled Receptors; Genetic Transcription; Genome; Genomics; Goals; HIV; Health; Health Status; Herpesviridae Infections; Homologous Gene; Human; Human Biology; Human Herpesvirus 8; Immunoglobulin G; In Vitro; Insecta; Kaposi Sarcoma; Ligands; Malignant Neoplasms; Malignant lymphoid neoplasm; Mammalian Cell; Measures; Mediating; Mediator of activation protein; Methods; Mus; Nude Mice; Oncogenic; Organoids; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Protein Engineering; Protein Family; Proteins; Protocols documentation; Public Health; Recombinants; Regulation; Resolution; Sampling; Second Messenger Systems; Signal Pathway; Signal Transduction; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Three-dimensional analysis; Tissues; Treatment Efficacy; Viral; Viral Genes; Virus; Work; base; cell transformation; chemokine; clinically relevant; extracellular; in vivo; insight; lytic replication; member; milligram; mouse model; nanobodies; novel therapeutic intervention; novel therapeutics; oral cavity epithelium; paracrine; particle; receptor; receptor binding; screening; single-cell RNA sequencing; targeted treatment; therapeutic evaluation; three dimensional cell culture; transcriptome; tumor; tumor growth; tumorigenesis

Project Summary/Abstract Despite being a pressing human health problem, very little has been done thus far to develop specific therapeutics against Kaposi’s sarcoma-associated Herpesvirus (KSHV) infection and its associated diseases. Interestingly, the KSHV genome carries a viral homolog of cellular G-protein coupled receptor (GPCR). As essential mediators of cell signaling, GPCRs are involved in nearly all aspects of human biology. Their clinical relevance is thus underscored by the fact that 30-40% of all FDA approved drugs target GPCRs. The KSHV GPCR (vGPCR) is essential for virus-mediated oncogenesis: its expression is sufficient to transform cells in vitro and induce tumor formation in vivo. The fact that vGPCR plays a key role in KSHV oncogenesis and that it is a member of protein family frequently targeted by FDA-approved drugs makes vGPCR a promising target for therapeutic intervention. We will use biochemical methods and signaling assays to understand structural insight of vGPCR and to develop novel therapeutic nanobodies for inhibiting the oncogenic function of vGPCR.

项目概要/摘要 尽管这是一个紧迫的人类健康问题，但迄今为止在开发具体的 针对卡波西肉瘤相关疱疹病毒（KSHV）感染及其相关疾病的治疗 疾病。有趣的是，KSHV 基因组携带细胞 G 蛋白偶联的病毒同源物 受体（GPCR）。作为细胞信号转导的重要介质，GPCR 涉及几乎所有方面 人类生物学。因此，30-40% 的 FDA 已批准的药物以 GPCR 为靶点。 KSHV GPCR (vGPCR) 对于病毒介导的病毒至关重要 肿瘤发生：其表达足以在体外转化细胞并在体内诱导肿瘤形成。 vGPCR 在 KSHV 肿瘤发生中发挥关键作用，并且它是蛋白质家族的一员 经常被 FDA 批准的药物靶向，使得 vGPCR 成为有希望的治疗靶点 干涉。我们将使用生化方法和信号分析来了解结构见解 vGPCR 并开发新型治疗性纳米抗体来抑制 vGPCR 的致癌功能 vGPCR。