Chemical synthesis and biological activity of peptides incorporating an ether bridge as a surrogate for a disulfide bond

Abstract

<p>Disulfide bridges contribute to the definition and rigidity of polypeptides, but they are inherently unstable in reducing environments and in the presence of isomerases and nucleophiles. Strategies to address these...</p>

Discovery of Methylene Thioacetal-Incorporated α-RgIA Analogues as Potent and Stable Antagonists of the Human α9α10 Nicotinic Acetylcholine Receptor for the Treatment of Neuropathic Pain

“…Designer disulfide mimetics can prevent disulfide bond scrambling and therefore represent powerful tools in disulfide-rich peptide drug discovery . Strategies including dicarba, saturated dicarba, alkyne, thioether, ether, diselenide (Sec), penicillamine-cysteine (Pen-Cys) hybrid, and triazole bridge replacement have been extensively applied in CTx modifications (Figure C). − However, such strategies lack broad applicability owing to incompatibility of the mimetic moiety with bioactivity and toxicity. Head-to-tail backbone cyclization is another investigated strategy to improve peptide stability through prevention of degradation as it stabilized the structure and reduced proteolysis susceptibility. − Nevertheless, the application of this method to RgIA resulted in obvious potency drop on α9α10 nAChR binding affinity. − …”

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…161 To date, however, ether-containing cyclic peptides are predominantly accessed by other cyclization reactions, with the ether moiety introduced as part of a pre-formed building block. 144,[162][163][164][165]…”

“…Ethers could be an interesting peptide bridging motif because they are flexible, have multiple conformations, and are more stable than disulfides or thioethers to reduction, oxidation, or nucleophiles, 144 yet there are limited examples of their use in peptide macrocyclization. Notably, biaryl ethers have played a role in the synthesis of many natural product peptides, in particular for antibiotic glycopeptides, such as vancomycin.…”

Chemo-Selective Cys–Pen Disulfide for Proximity-Induced Cysteine Cross-Linking

“…Disulfide-rich architectures are widely distributed in nature . Some of them have become valuable as pharmacological tools or therapeutics for numerous targets. − Cys–Cys disulfide bonds play an important role in stabilizing these disulfide-rich architectures’ tertiary and quaternary structure and making them sensitive to redox differences. , In addition, rationally designed targeted covalent inhibitors (TCI) attracted many concerns due to the prolonged residence time, increased potency, and enhanced selectivity. , Furthermore, covalent inhibitors may have potential applications in the area of intractable targets including highly charged pockets or shallow and large protein–protein interactions . We envisioned if we could combine these disulfide-rich architectures and the strategy of TCI to develop more a specific covalent inhibitor (or activators) via the thiol–disulfide interchange.…”