PDF(Pubmed)
Abstract：
Cyclic peptides present a robust platform for drug design, offering high specificity and stability due to their conformationally constrained structures. In this study, we introduce an updated version of the Cyclic Peptide Matching program (cPEPmatch) tailored for the identification of cyclic peptides capable of mimicking protein-glycosaminoglycan (GAG) binding sites. We focused on engineering cyclic peptides to replicate the GAG-binding affinity of antithrombin III (ATIII), a protein that plays a crucial role in modulating anticoagulation through interaction with the GAG heparin. By integrating computational and experimental methods, we successfully identified a cyclic peptide binder with promising potential for future optimization. MD simulations and MM-GBSA calculations were used to assess binding efficacy, supplemented by umbrella sampling to approximate free energy landscapes. The binding specificity was further validated through NMR and ITC experiments. Our findings demonstrate that the computationally designed cyclic peptides effectively target GAGs, suggesting their potential as novel therapeutic agents. This study advances our understanding of peptide-GAG interactions and lays the groundwork for future development of cyclic peptide-based therapeutics.
摘要：
环肽为药物设计提供了一个强大的平台，由于其构象受限的结构，提供高特异性和稳定性。在这项研究中,我们介绍了环肽匹配程序（cPEPmatch）的更新版本，该程序专门用于鉴定能够模拟蛋白质-糖胺聚糖（GAG）结合位点的环肽。我们专注于工程环肽以复制抗凝血酶III（ATIII）的GAG结合亲和力，一种通过与GAG肝素相互作用在调节抗凝作用中起关键作用的蛋白质。通过整合计算和实验方法，我们成功地确定了一种环肽结合剂，具有未来优化的潜力。MD模拟和MM-GBSA计算用于评估结合功效，辅以伞采样，以近似自由能景观。通过NMR和ITC实验进一步验证结合特异性。我们的发现表明，计算设计的环肽有效地靶向GAG，表明它们作为新型治疗剂的潜力。这项研究促进了我们对肽-GAG相互作用的理解，并为基于环肽的疗法的未来发展奠定了基础。
