Post‐Translational Backbone Engineering through Selenomethionine‐Mediated Incorporation of Freidinger Lactams

Abstract

Amino-γ-lactam (Agl) bridged dipeptides, commonly known as Freidinger lactams, have been shown to constrain peptide backbone topology and stabilize type II' β-turns. The utility of these links as peptide constraints has inspired new approaches to their incorporation into complex peptides and peptoids, all of which require harsh reaction conditions or protecting groups that limit their use on unprotected peptides and proteins. Herein, we employ a mild and selective alkylation of selenomethionine in acidic aqueous solution, followed by immobilization of the alkylated peptide on to bulk reverse-phase C silica and base-induced lactamization in DMSO. The utilization of selenomethionine, which is readily introduced by synthesis or expression, and the mild conditions enable selective backbone engineering in complex peptide and protein systems.

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

“…Many of the inherent limitations of DNA as the encoding element of DEL can be overcome through immobilization, and an approach termed reversible adsorption to solid support (RASS) has been developed to facilitate the covalent manipulation of macromolecules such as proteins and DNA in organic solvents . Non‐DNA encoding strategies, namely peptide nucleic acids (PNAs) can also be employed to overcome the inherent limitations of DNA as a encoding tag .…”

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

“…Many of the inherent limitations of DNA as the encoding element of DEL can be overcome through immobilization, and an approach termed reversible adsorption to solid support (RASS) has been developed to facilitate the covalent manipulation of macromolecules such as proteins and DNA in organic solvents . Non‐DNA encoding strategies, namely peptide nucleic acids (PNAs) can also be employed to overcome the inherent limitations of DNA as a encoding tag .…”

DNA Encoded Libraries: A Visitor's Guide

“…[19][20][21][71][72][73][74][75] This approach has also been applied to biomacromolecules to perform challenging synthetic modifications in an approach described as reversible adsorption to solid support (RASS). [76,77] As RASS based reactions mostly mimic typical organic conditions utilizing dry solvents and high concentrations of reagents, the Dawson and Baran groups envisioned the adaption of this technology to DEL to enable previously sluggish chemical reactivities. [78] They demonstrated that immobilizing DNA onto an inert, non-swelling, polystyrene-based quaternary ammonium support facilitates the rapid development of useful transformations including C (sp 2 )-C(sp 3 ) decarboxylative cross-couplings, the first DNAcompatible electrochemical reactions, and improved reductive amination conditions.…”