Effects of backbone cyclization on the pharmacokinetics and drug efficiency of the orally active analgesic conotoxin cVc1.1

Chronic pain is an undertreated epidemic affecting quality of life in at least 20% the global population, and CNS-related side effects, tolerance, addiction are common features current medications. ?-Conotoxin Vc1.1 potently elicits prolonged analgesia preclinical chronic constriction injury visceral hypersensitivity models neuropathic pain. A backbone-cyclized variant, cVc1.1, exhibits superior vitro stability orally active, but its vivo half-life disposition, both critical informing drug candidate progression, remain unexplored. Here, we investigate pharmacological influence peptidic bridge differentiating linear cyclic various PK/PD rodent models. While previous studies had indicated cyclization conferred increased for peptides exhibited similar half-lives oral bioavailabilities. The ratios free exposure metrics (Cmax × fu,p AUC0-inf fu,p) following dosing vs. their respective IC50s GABAB receptor were comparable indicating efficiency indexes. MALDI imaging, radiolabel, LC-MS biodistribution cVc1.1 rodents demonstrated that intact cyclopeptide several metabolites persist GI tract 4 h, long after plasma levels peptide fallen below target IC50. Biodistribution analyses IV administered 125I-labelled revealed accumulation primarily kidneys consistent with renal elimination, combined insignificant uptake brain, suggested a low likelihood effects.