Development of Broadly Applicable and Comprehensive Synthetic Method for <i>N</i>-Alkyl-Rich Drug-like Cyclic Peptides

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  • 高度に<i>N</i>-アルキル化されたドラッグライク環状ペプチドの一般合成法の開発

Abstract

<p>N-Alkylated cyclic peptides are an attractive modality for targeting intracellular PPI, but the lack of a sufficient synthetic method has prevented progress in the development of this modality. We have established a versatile and durable method for synthesizing highly N-alkylated drug-like cyclic peptides. This is the first reported method for synthesizing such peptides in parallel with a high success rate and acceptable purity, without the need for sequence-specific optimizations. In this study, we addressed three key challenges in setting up reaction conditions: (1) diketopiperazine (DKP) formation as a side reaction during Fmoc removal, (2) insufficient amide bond formation due to the steric hindrance of the N-Me amino acid, and (3) the instability of N-Me rich peptides under acidic conditions. Using this newly established method, we successfully synthesized thousands of cyclic peptides, greatly enhancing our understanding of their drug-likeness and enabling us to innovate the whole drug discovery process, from hit generation to lead optimization. Consequently, we discovered the clinical cyclic peptide LUNA18 (RAS inhibitor), demonstrating the value of cyclic peptides as a middle-size molecule modality.</p>

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