Synthesis of Hybrid Cyclic Peptoids and Identification of Autophagy Enhancer

Cyclic peptoids are potential candidates for diverse biological activities. However, applications of cyclic peptoids are limited by the synthetic difficulties, conformational flexibility of large cyclic peptoids, and lack of secondary amide in the backbone. Herein, an elegant methodology for the synthesis of small and medium-size cyclic hybrid peptoids is developed. ^α N-Alkyl and ^α N-acyl substituents in N-(2-aminoethyl)glycine monomers enforce intra- and intermolecular cyclization to form stable six- and 12-membered cyclic products, respectively. NMR studies show inter- and intramolecular hydrogen bonding in six- and 12-membered cyclic peptoids, respectively. Screening of a cyclic peptoid library resulted in the identification of a potential candidate that enhanced autophagic degradation of cargo in a live cell model. Such upregulation of autophagy using small molecules is a promising approach for elimination of intracellular pathogens and neurodegenerative protein aggregates.