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.

项目摘要/摘要 尽管这是一个迫在眉睫的人类健康问题，但到目前为止，在开发特定的 卡波西肉瘤相关疱疹病毒感染及其相关基因的治疗 疾病。有趣的是，KSHV基因组携带一种细胞G蛋白的病毒同源物 受体(GPCR)。GPCRs作为细胞信号转导的重要中介，几乎参与了细胞信号传导的各个方面 人类生物学的。因此，30%-40%的FDA 批准的药物针对GPCRs。KSHV gpr(Vgpr)在病毒介导下是必不可少的 致癌作用：它的表达足以在体外转化细胞并在体内诱导肿瘤形成。 VGPCR在KSHV致癌中起关键作用，是蛋白质家族的成员 FDA批准的药物的频繁靶点使vGPCR成为有希望的治疗靶点 干预。我们将使用生化方法和信号分析来理解结构洞察力 并开发新的治疗纳米抗体以抑制vGPCR的致癌功能 VGPCR。