Using the Ultrastable Cyclotide Scaffold to Modulate Protein-protein Interactions

使用超稳定环肽支架调节蛋白质-蛋白质相互作用

• 批准号: 10391445
• 负责人: Julio A Camarero
• 金额: $ 41.26万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391445
• 关键词: Amino Acids; Autoimmune Diseases; Biological; Biological Availability; Cell membrane; Cells; Characteristics; Chemicals; Cystine; Development; Disulfides; Drug Design; Drug Kinetics; Extracellular Protein; Family; Future; Health; Human; Libraries; Malignant Neoplasms; Membrane; Methods; Molecular; Molecular Target; Monoclonal Antibodies; Nature; Oral; Outcomes Research; Peptides; Pharmaceutical Preparations; Pharmacology; Plants; Predisposition; Property; Proteins; Scaffolding Protein; Screening for cancer; Source; Specificity; Structure; Therapeutic; Therapeutic Agents; Variant; Vertebral column; base; bioimaging; chemical synthesis; clinical development; drug development; extracellular; high throughput screening; human disease; immunogenic; improved; innovation; novel; peptide drug; pharmacokinetics and pharmacodynamics; polypeptide; protein protein interaction; response; scaffold; screening; small molecule; success; tool; tool development; tumor

The success of protein-based therapeutics is revolutionizing drug development. Unlike small molecule drugs, peptide and protein-based therapeutics can target with high selectivity and specificity defective protein-protein interactions involved in human disease. Despite their success, however, there are still numerous stability and delivery issues associated with their use as therapeutic agents. For example, monoclonal antibodies (one the most successful protein-based therapeutics with several blockbuster drugs on the market and many more in clinical development) can only target extracellular molecular targets due to their inability to cross biological membranes. They are also extremely expensive to produce and are not bioavailable due to their susceptibility to proteolytic degradation. These issues have led to the exploration of alternative protein scaffolds as a source for novel types of protein-based therapeutics. In response to this important challenge, the Camarero lab is using the ultra-stable cyclotide scaffold. Cyclotides are a new emerging family of large plant-derived backbone-cyclized polypeptides (≈30 amino acids long) that share a 3 disulfide-stabilized core characterized by an unusual knotted structure. They have several characteristics that make them ideal drug development tools. The main features of cyclotides are a remarkable stability due to the cystine knot, a small size making them readily accessible to chemical synthesis, and excellent tolerance to sequence variations. For example, the first cyclotide to be discovered, kalataB1, is an orally effective uterotonic, and other cyclotides have been also shown to be orally bioavailable and capable of crossing cell membranes to efficiently target intracellular interactions. In addition, cyclotides have been shown to be poorly immunogenic due to their highly constrained nature. Cyclotides thus appear as highly promising leads or frameworks for peptide drug design. Within this context, the Camarero lab is also exploring the cell penetrating properties of these interesting microproteins as well as ways to improve it. Furthermore, his lab is also studying their pharmacokinetic (PK) and pharmacodynamic (PD) properties and explore different approaches to improve their PK profiles and oral bioavailability. In addition, we are also exploring the potential of bioactive cyclotides to be used as selective and specific bioimaging tools for early detection of cancer tumors.

基于蛋白质的疗法的成功正在给药物开发带来革命性的变化。与小分子不同 基于药物、多肽和蛋白质的治疗药物具有高选择性和特异性缺陷 与人类疾病有关的蛋白质-蛋白质相互作用。然而，尽管他们取得了成功，仍然有 与它们作为治疗剂使用相关的许多稳定性和递送问题。例如, 单抗(最成功的基于蛋白质的疗法之一，有几个重磅炸弹 市场上的药物和更多临床开发中的药物)只能针对细胞外分子 由于它们不能穿过生物膜而成为靶标。它们也非常昂贵， 由于其对蛋白质分解降解的敏感性，因此不能被生物利用。这些问题 导致了对替代蛋白质支架的探索，作为基于蛋白质的新型材料的来源 治疗学。 为了应对这一重要挑战，卡马雷罗实验室正在使用超稳定的环肽支架。 环肽是一类新兴的大分子植物衍生主链环化多肽(≈30氨基) 酸长)，共用一个三二硫键稳定的核心，其特征是一种不寻常的打结结构。他们 有几个特点使它们成为理想的药物开发工具。的主要特点 由于半胱氨酸结的缘故，环肽具有显著的稳定性，其体积小，易于接触。 到化学合成，以及对序列变化的出色耐受性。例如，第一个环肽到 已发现，KalataB1是一种口服有效的强宫药，其他环类化合物也已被证明 口服生物利用度，并能够穿过细胞膜有效地靶向细胞内 互动。此外，环状化合物由于其高度的免疫原性而被证明是弱免疫原性的。 受约束的自然。因此，环类化合物被认为是非常有希望的多肽药物的先导或骨架。 设计。在这种情况下，卡马雷罗实验室也在探索这些细胞的穿透特性 有趣的微蛋白质以及改进它的方法。此外，他的实验室也在研究他们的 药代动力学(PK)和药效学(PD)特性，并探索不同的治疗方法 改善他们的PK资料和口服生物利用度。此外，我们还在探索潜在的 生物活性环类化合物作为选择性和特异性生物成像工具用于癌症早期检测 肿瘤。