Small cyclic sodium channel inhibitors.
Voltage-gated sodium (NaV) channels play crucial roles in a range of (patho)physiological processes. Much interest has arisen within the pharmaceutical industry to pursue these channels as analgesic targets following overwhelming evidence that NaV channel subtypes NaV1.7-NaV1.9 are involved in nociception. More recently, NaV1.1, NaV1.3 and NaV1.6 have also been identified to be involved in pain pathways. Venom-derived disulfide-rich peptide toxins, isolated from spiders and cone snails, have been used extensively as probes to investigate these channels and have attracted much interest as drug leads. However, few peptide-based leads have made it as drugs due to unfavourable physiochemical attributes including poor in vivo pharmacokinetics and limited oral bioavailability. The present work aims to bridge the gap in the development pipeline between drug leads and drug candidates by downsizing these larger venom-derived NaV inhibitors into smaller, more "drug-like" molecules. Here, we use molecular engineering of small cyclic peptides to aid in the determination of what drives subtype selectivity and molecular interactions of these downsized inhibitors across NaV subtypes. We designed a series of small, stable and novel NaV probes displaying NaV subtype selectivity and potency in vitro coupled with potent in vivo analgesic activity, involving yet to be elucidated analgesic pathways in addition to NaV subtype modulation.
['Peigneur|Steve|S|', 'da Costa Oliveira|Cristina|C|', 'de Sousa Fonseca|Flávia Cristina|FC|', 'McMahon|Kirsten L|KL|', 'Mueller|Alexander|A|', 'Cheneval|Olivier|O|', 'Cristina Nogueira Freitas|Ana|A|', 'Starobova|Hana|H|', 'Dimitri Gama Duarte|Igor|I|', 'Craik|David J|DJ|', 'Vetter|Irina|I|', 'de Lima|Maria Elena|ME|', 'Schroeder|Christina I|CI|', 'Tytgat|Jan|J|']
D000818:Animals D005260:Female D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D010446:Peptide Fragments D012604:Scorpion Venoms D061567:Voltage-Gated Sodium Channel Blockers D061566:Voltage-Gated Sodium Channels D014982:Xenopus laevis
Nociception Pain Cyclic peptide Cone snail toxin Spider toxin Voltage gated sodium channel