默克公司Anna Fryszkowska和Chihui An研究团队合作的最新研究，提出了对天然多肽和蛋白质位点进行选择性功能化改造的化学酶学策略。2022年6月17日出版的《科学》发表了这项成果。
研究人员研发了一种酶传递依赖性高位点选择性修饰天然肽的生物共轭策略。研究人员改造了青霉素G酰基转移酶以区分胰岛素的游离氨基部分（两个在氨基末端和一个内部赖氨酸），并以可编程方式操纵可切割的苯乙酰胺基团以形成受保护的胰岛素衍生物。这使得选择性和特异性化学连接能够合成均质的生物偶联物，与现有方法相比，提高了产量和纯度，并开辟了利用天然蛋白质功能化以获取生物探针或药物的途径。
据了解，新治疗方式的出现需要补充工具来有效生产原材料。由于固有复杂性和具有相似反应性特征官能团的重复残基存在，生物分子位点选择性修饰方法的可用性仍面临长期挑战。
附：英文原文
Title: A chemoenzymatic strategy for site-selective functionalization of native peptides and proteins
Author: Anna Fryszkowska, Chihui An, Oscar Alvizo, Goutami Banerjee, Keith A. Canada, Yang Cao, Duane DeMong, Paul N. Devine, Da Duan, David M. Elgart, Iman Farasat, Donald R. Gauthier, Erin N. Guidry, Xiujuan Jia, Jongrock Kong, Nikki Kruse, Katrina W. Lexa, Alexey A. Makarov, Benjamin F. Mann, Erika M. Milczek, Vesna Mitchell, Jovana Nazor, Claudia Neri, Robert K. Orr, Peter Orth, Eric M. Phillips, James N. Riggins, Wes A. Schafer, Steven M. Silverman, Christopher A. Strulson, Nandhitha Subramanian, Rama Voladri, Hao Yang, Jie Yang, Xiang Yi, Xiyun Zhang, Wendy Zhong
Issue&Volume: 2022-06-17
Abstract: The emergence of new therapeutic modalities requires complementary tools for their efficient syntheses. Availability of methodologies for site-selective modification of biomolecules remains a long-standing challenge, given the inherent complexity and the presence of repeating residues that bear functional groups with similar reactivity profiles. We describe a bioconjugation strategy for modification of native peptides relying on high site selectivity conveyed by enzymes. We engineered penicillin G acylases to distinguish among free amino moieties of insulin (two at amino termini and an internal lysine) and manipulate cleavable phenylacetamide groups in a programmable manner to form protected insulin derivatives. This enables selective and specific chemical ligation to synthesize homogeneous bioconjugates, improving yield and purity compared to the existing methods, and generally opens avenues in the functionalization of native proteins to access biological probes or drugs.
DOI: abn2009
Source: https://www.science.org/doi/10.1126/science.abn2009