Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

• Published in: Current opinion in chemical biology 2015-02, Vol.24, p.38-47
• Main Authors: Moon, Heejo, Lim, Hyun-Suk
• Format: Article
• Language: English
• Subjects: Animals; Biomimetics - methods; Chemistry Techniques, Synthetic - methods; Drug Discovery - methods; Humans; Protein Interaction Maps - drug effects; Protein Structure, Secondary; Proteins - chemistry; Proteins - metabolism; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 1367-5931; 1879-0402
• DOI: 10.1016/j.cbpa.2014.10.023

•We highlight recent development of small-molecule α-helix mimetics.•We review solid-phase synthesis of small-molecule α-helix mimetics.•We highlight HTS methods for the identification of small-molecule α-helix mimetics. α-Helices are the most common protein secondary structure and play a key role in mediating many protein–protein interactions (PPIs) by serving as recognition motifs. Given that aberrant α-helix-mediated PPIs are linked to various disease states, targeting such interactions with small-molecules represents an attractive strategy to develop therapeutic candidates for the related diseases. Over the last decade, significant efforts have been directed toward developing α-helix mimetic small-molecules that can modulate α-helix-mediated PPIs. In this review, we will highlight recent advances in the development of non-peptidic, small-molecule α-helix mimetics with a focus on library synthesis and screening methods to efficiently discover small-molecule α-helix mimetics.