Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models

Abstract

Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABA B receptor agonist that inhibits Ca v 2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABA B Rs expressed in dorsal root ganglion (DRG) sensory neurons.

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. − …”

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

“…Several studies have indicated that certain α-conopeptides act as agonists of the GABA B receptor resulting in analgesic effects [ 42 , 43 , 44 , 45 ]. This has led to questions regarding the role and necessity of α9-containing nAChRs in mediating α-conopeptide analgesia.…”

Diversity-Oriented A3-Macrocyclization for Studying Influences of Ring-Size and Shape of Cyclic Peptides: CD36 Receptor Modulators

“…A 3 -macrocyclization could be applicable for developing high-affinity binders for various biological targets. Moreover, the methods described for selective alkyne reduction may be of value for further exploration of cyclic peptide analogues possessing unsaturated cross-linkers. , …”

“…Moreover, the methods described for selective alkyne reduction may be of value for further exploration of cyclic peptide analogues possessing unsaturated cross-linkers. 40,41 The scavenger receptor CD36 plays roles in the regulation of the TLR2/6 heterodimer assembly, the activation of transcription of proinflammatory cytokines, and the production of NO and reactive oxygen species. 37,42 Cyclic azapeptides offer notable potency for reducing TLR-2 agonist-induced proinflammatory cytokines and chemokines by binding CD36 and inducing dissociation from the TLR complex.…”

“…1 N-(Boc)Alanine N′-Propargyl Hydrazide (39). A solution of Boc-Ala-azaPra-Ofm (38, 1 equiv, 0.82 g, 1.77 mmol) in MeCN (15 mL) was treated with diethylamine (27.4 equiv, 3.55 g, 5 mL, 48.5 mmol), stirred at room temperature for 1.5 h, and evaporated to a residue that was purified by flash chromatography 46 (40). A solution of Fmoc-D-Trp(Boc)-OH (1 equiv, 4.5 g, 8.55 mmol), TBTU (1 equiv, 2.74 g, 8.55 mmol), and DIEA (2 equiv, 2.82 mL, 17.1 mmol) in DMF (20 mL) under an argon atmosphere was stirred at room temperature for 30 min, treated dropwise with a solution of 2,4-dimethoxybenzyl alcohol (1.1 equiv, 1.58 g, 9.4 mmol) in DMF (5 mL), stirred at room temperature for 4 h, and diluted with EtOAc.…”