Technologies for Directed Evolution of Glycoaptamers

糖适体定向进化技术

• 批准号: 10721663
• 负责人: Isaac Jonathan Krauss
• 金额: $ 42.12万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721663
• 关键词: Acceleration; Acids; Affinity; Allergens; Atherosclerosis; Autoimmunity; Avidity; Bar Codes; Binding; Binding Sites; Biological; Biological Process; C-Type Lectins; CD209 gene; Carbohydrates; Categories; Cell Adhesion; Chemicals; Communicable Diseases; Complex; DNA; Defense Mechanisms; Diabetes Mellitus; Diagnostic; Directed Molecular Evolution; Disease; Elements; Evolution; Exhibits; Eye; Fibrosis; Galactose; Galactose Binding Lectin; Galectin 1; Generations; Geometry; Glycobiology; Goals; HIV Antibodies; HIV vaccine; Hand; Heart; Immunity; Immunosuppression; Individual; Internet; Interruption; Lectin; Libraries; Ligand Binding; Ligands; Link; Liver; Lung; Macrophage; Malignant Neoplasms; Mannose; Medicine; Methods; Modification; Names; Nucleic Acids; Pharmaceutical Chemistry; Pharmaceutical Preparations; Polymers; Polysaccharides; Process; Property; Protein-Carbohydrate Interaction; Proteins; RNA; Research; Resistance; Rheumatoid Arthritis; Role; Serum; Sialic Acids; Signal Transduction; Specificity; Technology; Testing; Validation; Variant; Vertebral column; Viral; Virus Diseases; Work; angiogenesis; aptamer; carbohydrate binding protein; carbohydrate receptor; chelation; desensitization; design; flexibility; glycosylation; immunoregulation; in vivo; inhibitor; interest; langerin; member; non-drug; nuclease; pathogen; protein function; rapid technique; response; scaffold; sialic acid binding Ig-like lectin; small molecule; sugar; therapeutic development; tool

Project Summary/Abstract The goal of this Focused Technology R01 project is to develop technologies for rapid discovery of inhibitors of carbohydrate-binding proteins (CBPs). Carbohydrate-protein interactions are critical in numerous processes including host-pathogen recognition, cell adhesion and cell signaling, cancer angiogenesis, immune suppression, heart/liver/lung/eye fibrosis, atherosclerosis, diabetes, and rheumatoid arthritis, to name a few examples. However, selective disruption of specific CBP interactions is challenging in vivo. CBPs generally bind weakly to individual glycans, with higher affinity (avidity) or specificity coming from multivalent interactions to clustered glycans or interactions with nearby non-carbohydrate elements. A given CBP also usually binds to various glycans. To untangle the complex web of CBP functions, it is important to have a way to rapidly develop a specific and potent inhibitor of a CBP that can be used in the relevant in vivo context. To this end, we propose two Aims: 1) to develop multivalent glyco-F-RNA aptamers, in which a nuclease-resistant, F-RNA backbone is evolved to present simple glycans in a manner that is selectively recognized by a CBP of interest; 2) to develop monovalent glyco- F-RNA aptamers, in which a simple glycan provides a binding “foothold” for the CBP of interest, which the evolved F-RNA component confers additional binding affinity and specificity through interactions auxiliary to the glycan-binding pocket.

项目总结/摘要 这个聚焦技术R 01项目的目标是开发快速发现的技术 碳水化合物结合蛋白（CBPs）的抑制剂。碳水化合物-蛋白质相互作用 在包括宿主-病原体识别、细胞粘附和细胞增殖在内的许多过程中至关重要。 信号传导，癌症血管生成，免疫抑制，心脏/肝脏/肺/眼睛纤维化， 动脉粥样硬化、糖尿病和类风湿性关节炎。然而，选择性 在体内破坏特异性CBP相互作用具有挑战性。CBP通常弱结合至 单个聚糖，具有来自多价相互作用的较高亲和力（亲合力）或特异性 成簇的聚糖或与附近的非碳水化合物元素的相互作用。一个CBP也 通常与各种聚糖结合。为了解开CBP功能的复杂网络，重要的是 有一种方法可以快速开发一种特异性和有效的CBP抑制剂， 与体内环境相关。为此，我们提出了两个目标：1）开发多价糖基-F-RNA 适体，其中核酸酶抗性的F-RNA骨架进化为呈现简单聚糖 以被感兴趣的CBP选择性识别的方式; 2）开发单价糖- F-RNA适体，其中简单聚糖为目标CBP提供结合“立足点”， 其中进化的F-RNA组分赋予额外的结合亲和力和特异性， 辅助聚糖结合口袋的相互作用。