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Orally active peptidic bradykinin B1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment.

Chronic pain is a universal health issue associated with numerous medical conditions, for example after severe burns or following major surgery. Compelling evidence suggests that bradykinin (BK) antagonists could be useful in treating chronic pain and inflammatory pain. Bradykinin and its homolog kallidin (lysyl-BK or KD), which are collectively known as kinins, participate in many pathophysiological insults. They are short-lived peptide mediators and the most potent endogenous pain inducers. Kinins are released during tissue injury or noxious stimulation and modulate pain through the activation of both the B1 and the B2 receptor, which are two G-protein-coupled receptors; the carboxypeptidase metabolites of kinins, des-Arg-BK and des-Arg-KD, activate the B1 receptor. [2b, 4] The B1 receptor stimulates the chronic phase of the inflammatory pain response, while the B2 receptor stimulates the acute phase owing to their differences in ligand dissociation, receptor desensitization, downregulation as well as internalization. Emerging evidence also suggests that the B1 receptor mediates various chronic pain responses through the activation of phospholipase C, thereby leading to the production of diacylglycerol and inositol triphosphate, which further activate protein kinase C and Ca mobilization. Numerous BK-antagonist peptides have been discovered from natural sources and structure–activity studies. Kinestatin isolated from frog skin and helokinestatin from lizard venom are examples of natural BK-antagonist peptides. Structure–activity studies have shown that removing the Cterminal Arg residue and concurrently replacing the penultimate residue Phe to Leu of bradykinin to des-Arg-[Leu]bradykinin or kallidin to des-Arg-[Leu]-kallidin (DALK) changes a bradykinin B2 receptor agonist to a B1 receptor antagonist (Figure 1). To increase potency and in vivo stability, several laboratories also developed BK antagonists