Rational design of small-molecule peptidomimetics for three pivotal protein secondary structures

Le résumé fourni par la source

In the pursuit of modulating protein-protein interactions (PPIs) using small molecules, the lack of studies addressing PPI modulation without structural information presents a significant hurdle. Although peptides have been utilized for this purpose, challenges such as permeability and stability persist, emphasizing the necessity for innovative small- molecule modulators. To target unexplored PPIs, we introduced a computational method encompassing three essential secondary structures of peptidomimetic scaffolds—α-helix, β- strand, and β-turn—serving as key recognition motifs for protein-protein interfaces. These scaffolds (1–3), systematically derived from a single pyrimidodiazepine skeleton, demonstrated precise alignment with each secondary structure, validated through in-silico analysis and X-ray crystallography. Subsequently, our pyrimidine-containing peptidomimetic scaffolds underwent rigorous evaluation via diverse phenotypic screenings. Positioned as invaluable chemical tools, these scaffolds hold immense potential for discovering novel PPI modulators. Our design strategy offers a rational approach, overcoming the inherent pharmacokinetic and pharmacodynamic limitations of traditional peptides. By leveraging structures and drug-like properties of small molecules, we aim to pioneer a new era in the design and synthesis of effective PPI modulators.

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