4 research outputs found
Recommended from our members
The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx-II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Nav1.7.
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
The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx-II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Nav1.7
The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx-II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Na<sub>v</sub>1.7
Spider
venom toxins, such as Protoxin-II (ProTx-II), have recently
received much attention as selective Na<sub>v</sub>1.7 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 <i>in vivo</i>. 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