Rolling Loop Scan: An Approach Featuring Ring-Closing Metathesis for Generating Libraries of Peptides with Molecular Shapes Mimicking Bioactive Conformations or Local Folding of Peptides and Proteins

Abstract

Libraries of loop-containing peptides (such as the one shown schematically) can be prepared from bis-N-alkylated peptides by ring-closing metathesis. In a general solid-phase procedure the peptides are accessible by site-specific N-alkylation. Since the amino acid side chains are not involved in cyclization, they remain available for interaction with, for example, a receptor.

Synthesis of Cyclic Dipeptides by Ring-Closing Metathesis

“…The application of RCM in the synthesis of larger cyclic peptides is the subject of other studies. [20,21] …”

Functional Reconstruction of Structurally Complex Epitopes using CLIPSTM Technology#

“…In order to understand better why small peptides (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) amino acids) are not stably folded, contrary to the proteins they were derived of, it is important to consider why proteins unfold. Proteins exist in a dynamic equilibrium between a folded (F) and an unfolded state (U) (Fig.…”

“…A variety of chemical methods is currently available for structural fixation of peptides into stable secondary structures, like -helices [16][17][18][19], -sheets [20], or -hairpins [21][22][23], either via backbone or side chain functionalities (SS, Br-SH, CO 2 H/NH 2 , metathesis, CLICK chemistry) [19,24,25]. Some of these require special protection/ deprotection protocols (CO 2 H/NH 2 ) or the addition of a catalyst (SS, metathesis, CLICK), since otherwise the reaction rates are too slow (SS, CLICK).…”

The cyclization of peptides and depsipeptides

“…The thrust of combinatorial library construction has moved macrocyclization steps into the wider echelons of contemporary organic chemistry and a popular recent development is to construct the cyclic constraints via ring closing olefine metathesis [218,219] as shown in Scheme 24.…”