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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

基本信息

批准号：
10606537
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606537
关键词：
Amino Acids Autoimmune Diseases Biological Biological Availability Cell membrane Cells Characteristics Chemicals Cyclization Cystine Development Disulfides Drug Design Drug Kinetics Extracellular Protein Family Future Health Human Imaging Device Libraries Malignant Neoplasms Marketing Membrane Methods Molecular Molecular Target Monoclonal Antibodies Nature Oral Outcomes Research Penetration Peptides Pharmaceutical Preparations Pharmacology Plants Predisposition Property Proteins Scaffolding Protein Screening for cancer Source Specificity Structure Therapeutic Therapeutic Agents Variant Vertebral column 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 development tumor

项目摘要

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.

基于蛋白质的治疗方法的成功正在彻底改变药物开发。不像小分子基于药物、肽和蛋白质的治疗剂可以高选择性和特异性靶向缺陷与人类疾病相关的蛋白质-蛋白质相互作用。然而，尽管他们取得了成功，与其作为治疗剂的用途相关的许多稳定性和递送问题。比如说，单克隆抗体（最成功的基于蛋白质的治疗方法之一，市场上的药物和临床开发中的许多药物）只能靶向细胞外分子由于它们不能穿过生物膜，因此它们是靶点。它们的价格也极其昂贵，产生并且由于它们对蛋白水解降解的敏感性而不具有生物利用度。这些问题已经导致了对替代蛋白质支架的探索，作为新型蛋白质基治疗学为了应对这一重要挑战，Camarero实验室正在使用超稳定的cyclotide支架。环肽是一个新出现的植物源性大骨架环化多肽家族（约30个氨基酸酸长），其共享以不寻常的打结结构为特征的3二硫化物稳定的核。他们有几个特点使它们成为理想的药物开发工具。的主要特点由于胱氨酸结，环肽具有显著的稳定性，小尺寸使其易于获得化学合成，以及对序列变异的出色耐受性。例如，第一个环肽， kalataB 1是一种口服有效的子宫收缩剂，其他环肽也被证明可口服生物利用并能够穿过细胞膜以有效靶向细胞内交互.此外，环肽类化合物由于其高度免疫原性而显示出免疫原性差。受约束的自然。因此，环肽类化合物似乎是非常有前途的肽类药物的先导物或框架设计在这种情况下，Camarero实验室也在探索这些细胞的细胞穿透特性。有趣的微蛋白以及改善它的方法。此外，他的实验室也在研究它们的药代动力学（PK）和药效学（PD）特性，并探索不同的方法，改善其PK特征和口服生物利用度。此外，我们也在探索用作癌症早期检测的选择性和特异性生物成像工具的生物活性环肽肿瘤的