Sciarretta Kimberly L, Gordon David J, Meredith Stephen C
The University of Chicago, Department of Pathology, Chicago, IL, USA.
Methods Enzymol. 2006;413:273-312. doi: 10.1016/S0076-6879(06)13015-3.
This review considers the design, synthesis, and mechanistic assessment of peptide-based fibrillogenesis inhibitors, mainly focusing on beta-amyloid, but generalizable to other aggregating proteins and peptides. In spite of revision of the "amyloid hypothesis," the investigation and development of fibrillogenesis inhibitors remain important scientific and therapeutic goals for at least three reasons. First, it is still premature to dismiss fibrils altogether as sources of cytotoxicity. Second, a "fibrillogenesis inhibitor" is typically identified experimentally as such, but these compounds may also bind to intermediates in the fibrillogenesis pathway and have hard-to-predict consequences, including improved clearance of more cytotoxic soluble oligomers. Third, inhibitors are valuable structural probes, as the entire field of enzymology attests. Screening procedures for selection of random inhibitory sequences are briefly considered, but the bulk of the review concentrates on rationally designed fibrillogenesis inhibitors. Among these are internal segments of fibril-forming peptides, amino acid substitutions and side chain modifications of fibrillogenic domains, insertion of prolines into or adjacent to fibrillogenic domains, modification of peptide termini, modification of peptide backbone atoms (including N-methylation), peptide cyclization, use of D-amino acids in fibrillogenic domains, and nonpeptidic beta-sheet mimics. Finally, we consider methods of assaying fibrillogenesis inhibitors, including pitfalls in these assays. We consider binding of inhibitor peptides to their targets, but because this is a specific application of the more general and much larger problem of assessing protein-protein interactions, this topic is covered only briefly. Finally, we consider potential applications of inhibitor peptides to therapeutic strategies.
本综述探讨了基于肽的纤维生成抑制剂的设计、合成及作用机制评估，主要聚焦于β-淀粉样蛋白，但也适用于其他聚集蛋白和肽。尽管“淀粉样蛋白假说”有所修正，但纤维生成抑制剂的研究与开发仍是重要的科学及治疗目标，原因至少有三点。其一，完全摒弃纤维作为细胞毒性来源仍为时过早。其二，“纤维生成抑制剂”通常是通过实验鉴定的，但这些化合物也可能与纤维生成途径中的中间体结合，并产生难以预测的后果，包括改善对细胞毒性更强的可溶性寡聚体的清除。其三，正如整个酶学领域所证明的，抑制剂是有价值的结构探针。本文简要考虑了用于筛选随机抑制序列的筛选程序，但综述的主要内容集中在合理设计的纤维生成抑制剂上。其中包括纤维形成肽的内部片段、纤维生成结构域的氨基酸取代和侧链修饰、在纤维生成结构域中或其附近插入脯氨酸、肽末端的修饰、肽主链原子的修饰（包括N-甲基化）、肽环化、在纤维生成结构域中使用D-氨基酸以及非肽类β-折叠模拟物。最后，我们考虑了检测纤维生成抑制剂的方法，包括这些检测中的陷阱。我们考虑了抑制肽与靶点的结合，但由于这是评估蛋白质-蛋白质相互作用这一更普遍且更大问题的具体应用，因此仅简要涉及该主题。最后，我们考虑了抑制肽在治疗策略中的潜在应用。
