Orally Active Peptidic Bradykinin B₁ Receptor Antagonists Engineered from a Cyclotide Scaffold for Inflammatory Pain Treatment

Abstract

Edible: By grafting natural peptide antagonists onto the cyclotide kalata B1, orally active peptides were engineered, which are potentially useful therapeutics for the treatment of inflammatory pain. For example, the entire loop 6 of kalata B1 was replaced with the peptidic bradykinin B1 receptor antagonist DALK (red in scheme) to obtain the cyclic bradykinin antagonist ckb‐kal.

T20K: An Immunomodulatory Cyclotide on Its Way to the Clinic

“…This unique three-dimensional fold confers them intrinsic stability to resist chemical, enzymatic and thermal degradation (Colgrave and Craik 2004). Therefore cyclotides have become attractive tools in chemical biology and drug development (Huang et al 2015), for instance as template for molecular grafting applications (Craik et al 2012) and for receptor ligand design (Koehbach et al 2013), since they exhibit activity following oral administration (Wong et al 2012).…”

“…The remarkable stability and hydrophobic surface properties of cyclotides render them well suited for oral administration (Wong et al 2012). Our data demonstrate significant therapeutic effects of T20K in the in vivo gold-standard model for MS, the murine EAE approach, after oral administration (Thell et al 2016).…”

Cyclotides: Overview and Biotechnological Applications

“…[9] For example, the first cyclotide to be discovered, kalata B1, is an orally effective uterotonic, [13] and other engineered cyclotides based on kalata B1 have also been shown to be orally bioactive. [14] In addition, some cyclotides can cross mammalian cell membranes [15] and are able to target intracellular protein interactions both in vitro and in vivo . [16] Cyclotides thus appear as promising leads or frameworks for the development of novel peptide-based diagnostics, therapeutics and research tools.…”

Asteropsins B–D, sponge-derived knottins with potential utility as a novel scaffold for oral peptide drugs

“…Several other knottins are currently undergoing preclinical or phase I/II clinical trials for the treatment of pain related diseases [7]. In addition to their potential as drug candidates, the use of knottins, especially cyclotides, has been extended to peptide engineering for the development of protease-resistant ligand scaffolds [3,4,8–12]. The cyclotide kalata B1, which exhibits stability towards pepsin, trypsin, and chymotrypsin, is a promising scaffold for the development of orally effective peptide drugs; however, the oral bio-availability of kalata B1 was found to be dramatically reduced when its head-to-tail cyclization was not performed [3,4].…”

“…In addition to their potential as drug candidates, the use of knottins, especially cyclotides, has been extended to peptide engineering for the development of protease-resistant ligand scaffolds [3,4,8–12]. The cyclotide kalata B1, which exhibits stability towards pepsin, trypsin, and chymotrypsin, is a promising scaffold for the development of orally effective peptide drugs; however, the oral bio-availability of kalata B1 was found to be dramatically reduced when its head-to-tail cyclization was not performed [3,4]. The linear knottins from squash (SE-EM and SE-EP), human agouti related protein (SE-AGAZ), and even hybrid recombinant knottins (SE-ET-TP-020 and SE-MC-TR-020) were found to be extensively degraded by chymotrypsin or trypsin [13–15].…”