Pfizer Worldwide Research and Development, San Diego, CA 92121,USA.
Bioorg Med Chem Lett. 2013 Oct 15;23(20):5680-3. doi: 10.1016/j.bmcl.2013.08.032. Epub 2013 Aug 13.
Although peptide-based molecules are known to have therapeutic potential, the generation of phage focused libraries to optimize peptides is effort-consuming. A 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.
虽然基于肽的分子被认为具有治疗潜力，但为了优化肽，生成噬菌体聚焦文库是一项费力的工作。本文开发了一种化学方法，用含有半胱氨酸的随机肽噬菌体展示文库来扩展马来酰亚胺缀合的肽。作为概念验证，合成了一个具有马来酰亚胺基团的 15 个氨基酸表皮生长因子受体 (EGFR) 结合肽，其 C 末端，并将其与含有半胱氨酸的文库偶联。经过淘选和筛选，发现了几个扩展肽，它们对 EGFR 的亲和力更高。该策略可广泛用于优化任何模式（肽、非天然肽、药物偶联物）的药效团，这些模式能够承载马来酰亚胺基团。
