Harnessing Aromatic‐Histidine Interactions through Synergistic Backbone Extension and Side Chain Modification

Yu, Zhen; Kreitler, Dale F.; Chiu, Yin Ting T.; Xu, Ruiwen; Bruchs, Austin T.; Bingman, Craig A.; Gellman, Samuel H.

doi:10.1002/ange.202308100

Title: Harnessing Aromatic‐Histidine Interactions through Synergistic Backbone Extension and Side Chain Modification

Journal Article · 28 August 2023 · Angewandte Chemie

DOI: https://doi.org/10.1002/ange.202308100 · OSTI ID:1997309

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Department of Chemistry University of Wisconsin-Madison Madison Wisconsin 53706 USA
National Synchrotron Light Source II Brookhaven National Laboratory Upton New York 11973 USA
Department of Biochemistry University of Wisconsin-Madison Madison Wisconsin 53706 USA

Abstract Peptide engineering efforts have delivered drugs for diverse human diseases. Side chain alteration is among the most common approaches to designing new peptides for specific applications. The peptide backbone can be modified as well, but this strategy has received relatively little attention. Here we show that new and favorable contacts between a His side chain on a target protein and an aromatic side chain on a synthetic peptide ligand can be engineered by rational and coordinated side chain modification and backbone extension. Side chain modification alone was unsuccessful. Binding measurements, high‐resolution structural studies and pharmacological outcomes all support the synergy between backbone and side chain modification in engineered ligands of the parathyroid hormone receptor‐1, which is targeted by osteoporosis drugs. These results should motivate other structure‐based designs featuring coordinated side chain modification and backbone extension to enhance the engagement of peptide ligands with target proteins.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: Michigan Economic Development Corporation (MEDC); Michigan Technology Tri-Corridor; National Institutes of Health (NIH); USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 1997309

Report Number(s):: BNL--224778-2023-JAAM; e202308100

Journal Information:: Angewandte Chemie, Journal Name: Angewandte Chemie Journal Issue: 40 Vol. 135; ISSN 0044-8249

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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