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

基本信息

批准号：
10643706
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
项目类别：
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/10643706
关键词：
3-Dimensional 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 Epithelium Etiology FDA approved G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genetic Transcription Genome Genomics Goals HIV HIV/AIDS 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 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 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

项目摘要

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/摘要尽管是一个紧迫的人类健康问题，但到目前为止，几乎没有做任何事情来开发特定的针对Kaposi的肉瘤相关疱疹病毒（KSHV）感染及其相关的治疗疾病。有趣的是，KSHV基因组具有偶联的细胞G蛋白的病毒同源物接收器（GPCR）。作为细胞信号的基本介体，GPCR几乎参与了所有方面人类生物学。因此，所有FDA中有30-40％批准的药物靶向GPCR。 KSHV GPCR（VGPCR）对于病毒介导的必不可少肿瘤发生：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肿瘤发生中起关键作用，并且它是蛋白质家族的成员经常以FDA批准的药物为目标，使VGPCR成为有希望的治疗目标干涉。我们将使用生化方法和信号测定来了解结构洞察 VGPCR并开发新的治疗性纳米剂，以抑制 VGPCR。