Backbone cyclization: A new method for conferring conformational constraint on peptides

Abstract

This article describes a new concept of medium- and long-range cyclization of peptides through “backbone cyclization.” In this approach, conformational constraints are conferred on a peptide by linking ω-substituted alkylidene chains replacing N^α or C^α hydrogens in a peptidic backbone. Backbone cyclization, which is divided into N-backbone and C-backbone cyclizations, allow for new modes of cyclization in addition to the classical ones that are limited to cyclization through the side chains and/or the amino or carboxyl terminal groups. The article also describes the application of the N-backbone cyclization to the active region of substance P. Conformational constraints of this peptide by the classical cyclization modes led to inactive analogues whereas N-backbone cyclization provided an active, selective, and metabolically stable analogue.