Patients with chronic pain are underserved by existing treatments, resulting in high social and economic costs, and new approaches to the management of pain are urgently needed. A number of ion channel proteins are suggested as potential targets for the treatment of pain, but existing small molecule inhibitors often lack specificity and exhibit off-target effects. Peptides belonging to the inhibitor cystine knot (ICK) class of peptides often target these ion channels with considerable potency and specificity, making them a promising lead in the development of new drugs for pain. However, their topologically-complex structure defined by three interlocking disulfide bonds presents a synthetic challenge, and their folding pathway is poorly understood. As a result, folding yields for these peptides are often low. We are investigating the oxidative folding of the ICK peptide Protoxin-II (1) and its interactions with the voltage-gated sodium channel Nav1.7. Using ion-mobility mass spectrometry and patch-clamp electrophysiology, we have demonstrated the importance of the folding conditions for the activity of the resulting peptide and solved the structure of the fully-folded peptide by X-ray crystallography. Using this information, we have designed and synthesized analogues of Protoxin-II incorporating unnatural amino acids; these have allowed us to study the oxidative folding pathway of the peptide and present opportunities to investigate the mechanism of its inhibition of Nav1.7. These results will help in the design of new compounds to treat chronic pain.

Chemical biology approaches to understanding the structure and function of Protoxin-II

2019 Fall National Meeting

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