Santoso Buyung, Murray Brion W
Pfizer Worldwide Research and Development, 10646 Science Center Dr, San Diego, CA, 92121, USA.
Methods Mol Biol. 2015;1248:267-76. doi: 10.1007/978-1-4939-2020-4_18.
Peptide-based molecules are known to have therapeutic utility, but the generation of phage-focused libraries to optimize peptide properties and functionality is challenging. Genetic approaches are limited to peptide extension on the peptide termini. Current chemical methods are technically challenging and time-consuming. A new chemical method is developed to extend a maleimide-conjugated peptide with a cysteine-containing random peptide phage display library. As a proof of concept, a 15-mer epidermal growth factor receptor (EGFR)-binding peptide was synthesized with a maleimide group at its C-terminus and then conjugated to the cysteine-containing library. After panning and screening, several extended peptides were discovered and tested to have a higher affinity to EGFR. This strategy can have broad utility to optimize pharmacophores of any modalities (peptides, unnatural peptides, drug conjugates) capable of bearing a maleimide group.
基于肽的分子具有治疗用途，但生成以噬菌体为重点的文库以优化肽的性质和功能具有挑战性。基因方法仅限于在肽末端进行肽延伸。目前的化学方法在技术上具有挑战性且耗时。已开发出一种新的化学方法，用含半胱氨酸的随机肽噬菌体展示文库来延伸马来酰亚胺共轭肽。作为概念验证，合成了一种15聚体表皮生长因子受体（EGFR）结合肽，其C末端带有马来酰亚胺基团，然后与含半胱氨酸的文库共轭。经过淘选和筛选，发现了几种延伸肽，并测试其对EGFR具有更高的亲和力。该策略可广泛用于优化任何能够带有马来酰亚胺基团的形式（肽、非天然肽、药物共轭物）的药效基团。
