Hartlieb Matthias, Williams Elizabeth G L, Kuroki Agnès, Perrier Sébastien, Locock Katherine E S
Department of Chemistry, The University of Warwick, Coventry CV4 7AL. United Kingdom.
CSIRO Manufacturing, Clayton, VIC 3168. Australia.
Curr Med Chem. 2017;24(19):2115-2140. doi: 10.2174/0929867324666170116122322.
Peptides and proteins control and direct all aspects of cellular function and communication. Having been honed by nature for millions of years, they also typically display an unsurpassed specificity for their biological targets. This underlies the continued focus on peptides as promising drug candidates. However, the development of peptides into viable drugs is hampered by their lack of chemical and pharmacokinetic stability and the cost of large scale production. One method to overcome such hindrances is to develop polymer systems that are able to retain the important structural features of these biologically active peptides, while being cheaper and easier to produce and manipulate chemically. This review illustrates these principles using examples of polymers designed to mimic antimicrobial host-defence peptides. The host-defence peptides have been identified as some of the most important leads for the next generation of antibiotics as they typically exhibit broad spectrum antimicrobial ability, low toxicity toward human cells and little susceptibility to currently known mechanisms of bacterial resistance. Their movement from the bench to clinic is yet to be realised, however, due to the limitations of these peptides as drugs. The literature provides a number of examples of polymers that have been able to mimic these peptides through all levels of structure, starting from specific amino acid sidechains, through to more global features such as overall charge, molecular weight and threedimensional structure (e.g. α-helical). The resulting optimised polymers are able retain the activity profile of the peptides, but within a synthetic macromolecular construct that may be better suited to the development of a new generation of antimicrobial therapeutics. Such work has not only produced important new leads to combat the growing threat of antibiotic resistance, but may also open up new ways for polymers to mimic other important classes of biologically active peptides.
肽和蛋白质控制并指导细胞功能和通讯的各个方面。经过数百万年的自然锤炼，它们通常对其生物靶点表现出无与伦比的特异性。这也是人们持续关注肽作为有前景的药物候选物的原因所在。然而，肽类药物的开发受到其化学和药代动力学稳定性不足以及大规模生产成本高昂的阻碍。克服这些障碍的一种方法是开发聚合物系统，该系统能够保留这些生物活性肽的重要结构特征，同时更便宜且更易于化学合成和操作。本综述通过设计用于模拟抗菌宿主防御肽的聚合物实例来说明这些原理。宿主防御肽已被确定为下一代抗生素的一些最重要的先导物，因为它们通常具有广谱抗菌能力、对人类细胞的低毒性以及对目前已知的细菌耐药机制的低敏感性。然而，由于这些肽作为药物存在局限性，它们从实验室到临床的转化尚未实现。文献提供了许多聚合物的例子，这些聚合物能够在各个结构层面模拟这些肽，从特定的氨基酸侧链，到更宏观的特征，如整体电荷、分子量和三维结构（如α螺旋）。由此产生的优化聚合物能够保留肽的活性特征，但存在于一个可能更适合开发新一代抗菌治疗药物的合成大分子结构中。此类工作不仅产生了应对抗生素耐药性日益增长威胁的重要新先导物，还可能为聚合物模拟其他重要类别的生物活性肽开辟新途径。
