Peptides to peptidomimetics: towards the design and synthesis of bioavailable inhibitors of oligosaccharyl transferase

Abstract

Oligosaccharyl transferase (OT) is the enzyme responsible for asparagine-linked glycosylation in the lumen of the endoplasmic reticulum, which is a subcellular compartment within eukaryotic cells. Inhibition of this enzyme within a cellular environment would provide a valuable investigative tool for glycobiology. Due to the limitations of peptides, none of the existing peptide-based inhibitors of OT demonstrate activity in cell-based enzyme assays. We report herein the design, synthesis and preliminary biological characterization of a family of peptidomimetics that inhibit OT with Ki values in the nanomolar range. The hexapeptide Bz-Dab-Ala-Thr-Val-Thr-Nph-NH2 (Ki = 69 nM) was used as the prototype for the design of bioavailable inhibitors. Several aminobenzoic acid spacer groups were evaluated as potential isosteres of the Val-Thr dipeptide unit and the peptidomimetic incorporating 3-aminobenzoic acid proved to inhibit OT with similar potency to the parent compound (Ki = 84 nM). Further modifications explored the effects of size, hydrophobicity and conformational rigidity on enzyme affinity. This study yielded a family of potent non-peptidic inhibitors that are viable candidates for the in vivo inhibition of OT.

Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells

“…Although peptidomimetics that block N-linked glycosylation have been developed 24,25 , cell permeability for these inhibitors remains a challenge. We therefore developed a tiered high throughput screening (HTS) methodology to identify small molecule inhibitors of protein N-linked glycosylation.…”

Structure-Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Antiangiogenic and Melanoma’ Antitumor Activities

“…Active ion transporters have been developed from acyclic octapeptides comprising MABA [26] and MABA monopeptide esters showed promising antimicrobial activity towards gram-positive bacteria [27]. Different MABA analogs showed anticoagulant and antiplatelet activities [28], hexapeptides with MABA were evaluated as potential isosteres of the Val-Thr dipeptide unit and a peptidomimetic incorporating MABA proved to effectively inhibit oligosaccharyl transferase, the enzyme responsible for asparagine-linked glycosylation in the lumen of the endoplasmic reticulum [29].…”

Olefin ring-closing metathesis as a powerful tool in drug discovery and development – potent macrocyclic inhibitors of the hepatitis C virus NS3 protease

“…Such interactions play a key role in numerous cellular functions (e.g. protein glycosylation [2], intracellular recognition [3], proteolysis and others) and can be of particular relevance in drug discovery. However, unlike the structurally unique peptides found at the contact points between two large biomolecules, short peptides are conformationally heterogeneous and exhibit low affinity for their intended binding sites.…”