Design, synthesis, and analysis of macrobicyclic peptides for targeting the Gαi protein.

Autor: Pepanian A; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, Bonn, Germany., Binbay FA; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, Bonn, Germany., Pei D; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, USA., Imhof D; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
Jazyk: angličtina
Zdroj: Journal of peptide science : an official publication of the European Peptide Society [J Pept Sci] 2024 Jun; Vol. 30 (6), pp. e3565. Date of Electronic Publication: 2024 Jan 17.
DOI: 10.1002/psc.3565
Abstrakt: Bicyclic peptides are important chemical tools that can function, for example, as bioactive ligands switching on/off signaling pathways mediated by guanine nucleotide-binding proteins as bicycles are more broadly applicable. Despite their relevance in medicinal chemistry, the synthesis of such peptides is challenging, and the final yield is highly dependent on the chemical composition and physicochemical properties of the scaffold. We recently discovered novel, state-specific peptide modulators targeting the Gαi protein, namely, GPM-2/GPM-3, by screening a one-bead-two-compound combinatorial library. A more detailed analysis, including sequence alignments and computer-assisted conformational studies based on the hit compounds, revealed the new peptide 10 as a potential macrobicyclic Gαi ligand sharing high sequence similarity to the known Gαi modulators. The Gαs protein was included in this study for comparison and to unravel the criteria for the specificity of modulator binding to Gαi versus Gαs. This work provides in-depth computer-assisted experimental studies for the analysis of novel macrobicyclic, library-derived Gαi protein ligands. The sequence and structural comparison of 10 with the lead compounds GPM-2 and GPM-3 reveals the importance of the size and amino acid composition of one ring of the bicyclic system and suggests features enhancing the binding affinity of the peptides to the Gαi protein.
(© 2024 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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