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.

与小分子不同，基于蛋白质的疗法的成功正在彻底改变药物开发。 基于肽和蛋白质的疗法可以以高选择性和特异性缺陷为目标 然而，尽管它们取得了成功，但仍然存在与人类疾病有关的蛋白质-蛋白质相互作用。 许多与它们用作治疗剂相关的稳定性和递送问题。 单克隆抗体（最成功的基于蛋白质的疗法之一，具有多种重磅炸弹 市场上以及更多处于临床开发中的药物）只能靶向细胞外分子 由于它们无法穿过生物膜，因此它们的成本也极其昂贵。 由于它们对蛋白水解降解敏感，因此无法产生这些问题。 导致了对替代蛋白质支架的探索，作为新型蛋白质基材料的来源 疗法。 为了应对这一重要挑战，Camarero 实验室正在使用超稳定的环肽支架。 环肽是一个新兴的大型植物衍生主链环化多肽家族（约 30 个氨基酸） 酸长），共享一个 3 个二硫键稳定的核心，其特征是不寻常的打结结构。 它们具有多种特性，使其成为理想的药物开发工具。 由于胱氨酸结，环肽具有显着的稳定性，尺寸小使其易于接近 化学合成，以及对序列变异的良好耐受性，例如第一个环肽。 被发现 kalataB1 是一种口服有效的子宫收缩剂，其他环肽也被证明可以 具有口服生物利用度并能够穿过细胞膜有效靶向细胞内 此外，环肽由于其高度的相互作用而被证明其免疫原性较差。 因此，环肽似乎是肽药物的非常有前途的先导化合物或框架。 在此背景下，Camarero 实验室也在探索这些材料的细胞穿透特性。 有趣的微生物蛋白质以及改进它的方法此外，他的实验室也在研究它们。 药代动力学 (PK) 和药效学 (PD) 特性，并探索不同的方法 此外，我们还在探索其潜力。 生物活性环肽可用作癌症早期检测的选择性和特异性生物成像工具 肿瘤。