χ-Conopeptide Pharmacophore Development: Toward a Novel Class of Norepinephrine Transporter Inhibitor (Xen2174) for Pain

Abstract

Norepinephrine (NE) amplifies the strength of descending pain inhibition, giving inhibitors of spinal NET clinical utility in the management of pain. chi-MrIA isolated from the venom of a predatory marine snail noncompetitively inhibits NET and reverses allodynia in rat models of neuropathic pain. An analogue of chi-MrIA has been found to be a suitable drug candidate. On the basis of the NMR solution structure of this related peptide, Xen2174 (3), and structure-activity relationships of analogues, a pharmacophore model for the allosteric binding of 3 to NET is proposed. It is shown that 3 interacts with NET predominantly through amino acids in the first loop, forming a tight inverse turn presenting amino acids Tyr7, Lys8, and Leu9 in an orientation allowing for high affinity interaction with NET. The second loop interacts with a large hydrophobic pocket within the transporter. Analogues based on the pharmacophore demonstrated activities that support the proposed model. On the basis of improved chemical stability and a wide therapeutic index, 3 was selected for further development and is currently in phase II clinical trials.

Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

“…For instance, ω-conotoxin MVIIA [C(6)C(6)CC(3)C(4)C] (the only FDA-approved venomderived synthetic peptide, marketed under the name Prialt) (53) and ω-conotoxin CVID [C(6)C(6)CC(3)C(6)C] (phase II clinical trials) (54) both contain the inhibitor cystine knot (ICK) motif where cysteine residues are disposed in a C-C-CC-C-C pattern with a I-IV, II-V, III-VI connectivity. Also, conotoxins such as χ-conotoxin MrIA [(3)CC(4)C(2)C; I-III, II-IV; phase II] are important drug leads (55). Despite a weak correlation between gene superfamilies and pharmacological properties, some functional redundancy among members of a same superfamily exists (56).…”

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

“…Pharmacophore models have lead to the discovery of XEN2174 compounds as Norepinephrine Transporter (NETa) and are in phase II clinical trials as pain killer (34). Pharmacophores have been developed for screening transforming growth factor b (ALK5) receptor inhibitors (35), Checkpoint1 kinase inhibitors (36) by retrieving potent molecules from potent databases like specs, NCI, Maybridge, and CNPD.…”

Stabilization of the Cysteine‐Rich Conotoxin MrIA by Using a 1,2,3‐Triazole as a Disulfide Bond Mimetic

“…The most active analogues 7 and 9 were also equally active compared with MrIA in a neuropathic pain study using a rat model sciatic nerve injury assay (Fig 5,6S). [19] The activity loss in 2-5 is due to the sensitivity of the turn region to topological changes, [19][20] likely to occur when introducing a 1,2,3-triazole ring in place of the Cys4-Cys10 disulfide bond. The triazole orientation appears to be of importance for NET activity (compare the more potent peptides 7, 9 with 6, 8).…”

“…In contrast, the length of the bridge, which differed by one CH2 group, plays a minor role (compare 7 vs. 9). These structural effects, were studied by secondary H NMR shift comparison [19] of MrIA and analogues 2-9; this demonstrated that inactive analogues 2-5 suffer from strong perturbation of the overall backbone structure ( Figure 1A). In contrast, active analogues 6-9 showed good H shift correlation compared to MrIA, particularly in the critical GYKL turn region [20] ( Figure 1B).…”

“…An overlay of their sheet regions (RMSD, 0.3Å) and the side chains of the pharmacophore (Tyr7, Lys8 and Leu9) showed high conservation (RMSD of 0.24 Å across backbone and  carbons), with side chain orientation as described for MrIA and 1. [19,21] Disulfide folded peptides with rigid structures and herewith limited access to cleavage sites, possess improved proteolytic stability [22] suggesting that degradation likely involves partial disulfide reduction / disulfide scrambling. [4a] Indeed, peptide 1 undergoes isomerisation, partial reduction, adduct formation and dimerization in the presence of thiols (GSH) and is unstable in plasma [23] (Fig 2, 7S).…”