Abstract
Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate.
Highlights
Peptide toxins hold considerable promise as novel therapeutics due to the potency and specificity with which they interact with their biological targets, low cost of synthesis, and largely wellunderstood metabolic pathways.[1]
In the naturally occurring lantibiotics, the lanthionine sought to explore the effects of subtle changes in peptide conformation arising from replacing each of the naturally occurring disulfide bridged rings in turn with a thioether linked ring on the binding of these peptides to hNav1.7 ion channels residues are present as the meso-(2R,6S) diastereoisomer
We report the synthesis of three synthetic analogues of the inhibitory cystine knot (ICK) scaffold spider toxin ProTx-II, where each of the three disulfide bridges is regioselectively replaced by a thioether linkage
Summary
Peptide toxins hold considerable promise as novel therapeutics due to the potency and specificity with which they interact with their biological targets, low cost of synthesis, and largely wellunderstood metabolic pathways.[1] These peptides are often cysteine-rich and contain intricate disulfide bonding patterns that are crucial for their biological activity.[2] Despite these encouraging properties, to date only one peptide toxin-based therapeutic (Ziconitide, marketed as Prialt) has been approved for clinical use.[3] This is largely due to commonly encountered problems in the in vivo stability of peptide toxins. Both unsaturated[8,9] and saturated[10] dicarba-bridges have been used as disulfide bond replacements in cystine-rich toxins, using either
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