Structure-activity relationships of ?-conotoxins at N-type voltage-sensitive calcium channels

Abstract

Due to their selectivity towards voltage-sensitive calcium channels (VSCCs) omega-conotoxins are being exploited as a new class of therapeutics in pain management and may also have potential application in ischaemic brain injury. Here, the structure-activity relationships (SARs) of several omega-conotoxins including GVIA, MVIIA, CVID and MVIIC are explored. In addition, the three-dimensional structures of these omega-conotoxins and some structurally related peptides that form the cysteine knot are compared, and the effects of the solution environment on structure discussed. The diversity of binding and functional assays used to measure omega-conotoxin potencies at the N-type VSCC warranted a re-evaluation of the relationship between these assays. With one exception, [A22]-GVIA, this analysis revealed a linear correlation between functional (peripheral N-type VSCCs) and radioligand binding assays (central N-type VSCCs) for the omega-conotoxins and analogues that were tested over three studies. The binding and functional results of several studies are compared in an attempt to identify and distinguish those residues that are important in omega-conotoxin function as opposed to those that form part of the structural scaffold. Further to determining what omega-conotoxin residues are important for VSCC binding, the range of possible interactions between the ligand and channel are considered and the factors that influence the selectivity of MVIIA, GVIA and CVID towards N-type VSCCs examined.

Inhibition of the Norepinephrine Transporter by the Venom Peptide χ-MrIA

“…Tyr-7, Lys-8, Leu-9, and to a lesser extent His-11 therefore seem likely to directly interact with the transporter, whereas Gly-6 probably plays a structural role to allow the correct orientation of the other residues in the loop for better NET binding. The involvement of tyrosine and lysine residues in the high affinity interaction of other peptide toxins with their targets has been reported previously (48,49), warranting further investigation into -MrIA's use of these residues as high affinity binding determinants in experiments with additional analogs. Phenylalanine was found to be able to largely substitute for Tyr-7, indicating that the hydroxyl group of the tyrosine residue is not of critical importance for binding.…”

“…Phenylalanine was found to be able to largely substitute for Tyr-7, indicating that the hydroxyl group of the tyrosine residue is not of critical importance for binding. This stands in contrast to its role in the interaction of the -conotoxins with the Ca v 2.3 channel (48). The replacement of arginine with lysine at position 8 had a relatively small detrimental effect on potency, showing that the side-chain charge may be a key determinant for binding at this position and that length is less influential.…”

Novel ω-Conotoxins from Conus catus Discriminate among Neuronal Calcium Channel Subtypes

“…In contrast, loop 4 is oriented parallel to loop 2 in MVIIA and MVIIC and away from loop 2 in GVIA (18,30,53,54). The presence of two hydrogen bonds between loops 2 and 4 in CVID favor loop 4 in this orientation, whereas hydrogen bonds between loops 2 and 4 have not been reported previously for GVIA, MVIIA or MVIIA.…”

Cardiovascular and autonomic effects of ω‐conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays

“…o-Conotoxins MVIIA and CVID were synthesized by the Centre for Drug Design and Development, The University of Queensland (St Lucia, Qld, Australia) Nielsen et al, 2000). MVIIA and CVID were dissolved in 0.9% saline (sterile saline for i.t.…”