A chemoenzymatic strategy for site-selective functionalization of native peptides and proteins

Autor: 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
Rok vydání: 2022
Předmět:
Zdroj: Science (New York, N.Y.). 376(6599)
ISSN: 1095-9203
Popis: 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.
Databáze: OpenAIRE
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