Fischer P M
Cyclacel Limited, Dundee, Scotland, UK.
Curr Protein Pept Sci. 2003 Oct;4(5):339-56. doi: 10.2174/1389203033487054.
Physiological processes are regulated to a large extent by physical and chemical interactions between polypeptides. Although many small molecules have been discovered that can modulate such interactions and may be useful as drugs, the design of these agents purely from the knowledge of the details of a given protein-protein interaction, or through screening, remains difficult. Therefore, the peptidomimetic process, which aims at using peptides derived from either polypeptide binding partner directly, or after modification to improve affinity and physicochemical properties, continues to be attractive. The vast majority of naturally occurring polypeptides are composed of L-amino acids. Because natural proteins need to be metabolised, L-amino acid polypeptides are very prone to proteolytic degradation, a property that severely limits their therapeutic application. The proteolytic machinery is not well equipped to deal with D-amino acid polypeptides, however, and it is this finding above all else that has spurned research into stereochemical and directional manipulation of peptide chains. The expectation has been that systematic inversion of the stereochemistry at the peptide backbone alpha-carbon atoms, if accompanied by chain reversal, should yield proteolytically stable retro-inverso peptide isomers, whose side chain topology, in the extended conformation, corresponds closely to that of a native sequence, and whose biological activity emulates that of a parent polypeptide. The actual structural implications of modifying amino acid stereochemistry and peptide bond direction are reviewed critically here and the reasons for the lack of general success with this strategy are discussed. The application of polypeptides is particularly pertinent to synthetic vaccine design. Interestingly, the retro-inverso strategy has been more successful for immunological applications than elsewhere; recent finding are collated in this review. Partial rather than global retro-inversion holds much promise since the loss of crucial backbone hydrogen-bonding through peptide bond reversal can be avoided, while still permitting stabilisation of selected hydrolysis-prone peptide bonds. Generically applicable synthetic methods for such partially modified retro-inverso peptides are not as yet available; progress towards this goal is also summarised.
生理过程在很大程度上受多肽之间物理和化学相互作用的调节。尽管已经发现了许多能够调节此类相互作用且可能用作药物的小分子，但仅根据给定蛋白质-蛋白质相互作用的详细知识或通过筛选来设计这些药物仍然很困难。因此，拟肽过程仍然具有吸引力，该过程旨在使用直接源自多肽结合伴侣的肽，或经过修饰以提高亲和力和物理化学性质的肽。绝大多数天然存在的多肽由L-氨基酸组成。由于天然蛋白质需要进行代谢，L-氨基酸多肽非常容易发生蛋白水解降解，这一特性严重限制了它们的治疗应用。然而，蛋白水解机制并不擅长处理D-氨基酸多肽，正是这一发现推动了对肽链立体化学和定向操纵的研究。人们期望，如果在肽主链α-碳原子处进行立体化学的系统反转并伴有链反转，应该会产生蛋白水解稳定的反向异构肽异构体，其在伸展构象中的侧链拓扑结构与天然序列的侧链拓扑结构密切对应，并且其生物活性模拟亲本多肽的生物活性。本文对修饰氨基酸立体化学和肽键方向的实际结构影响进行了批判性综述，并讨论了该策略缺乏普遍成功的原因。多肽的应用在合成疫苗设计中尤为相关。有趣的是，反向异构策略在免疫应用中比在其他方面更成功；本文综述了最近的研究发现。部分而非全局的反向异构具有很大的前景，因为可以避免因肽键反转而失去关键的主链氢键，同时仍能使选定的易水解肽键稳定。目前还没有适用于此类部分修饰的反向异构肽的通用合成方法；本文也总结了在这一目标上取得的进展。
