Novel Amphibian Bowman–Birk-Like Inhibitor with Antioxidant and Anticoagulant Effects Ameliorates Pancreatitis Symptoms in Mice

Abstract

Acute pancreatitis (AP) is a serious inflammatory disorder and still lacks effective therapy globally. In this study, a novel Ranacyclin peptide, Ranacin, was identified from the skin of Pelophylax nigromaculatus frog. Ranacin adopted a compact βhairpin conformation with a disulfide bond (Cys5−Cys15). Ranacin was also demonstrated effectively to inhibit trypsin and have anticoagulant and antioxidant activities in vitro. Furthermore, the severity of pancreatitis was significantly alleviated in L-Arg-induced AP mice after treatment with Ranacin. In addition, structure−activity studies of Ranacin analogues confirmed that the sequences outside the trypsin inhibitory loop (TIL), especially at the C-terminal side, might be closely associated with the efficacy of its trypsin inhibitory activity. In conclusion, our data suggest that Ranacin can improve pancreatic injury in mice with severe AP through its multi-activity. Therefore, Ranacin is considered a potential drug candidate in AP therapy.

An Effective Modification Strategy to Build Multifunctional Peptides Based on a Trypsin Inhibitory Peptide of the Kunitz Family

“…Based on shared characteristics such as structural domains, sequence homology, reactive site similarities, and mechanistic properties, these inhibitors can be categorised into distinct types, including but not limited to Bowman-Birk- [33], , and Kazaltype inhibitors [35]. For instance, Bowman-Birk inhibitors were identified in Pelophylax frogs [36], Kunitz-type inhibitors have been isolated from both tomato [27] and ranid frogs [8], and Kazal-type inhibitors were extracted from Phyllomdusa frogs [37]. To date, the Kunitz-type inhibitors have earned the least attention among these three inhibitor types.…”

“…Within the extensive array of identified Kunitz-type inhibitors, those derived from animals hold particular importance in the exploration of structure-activity relationships [36,[38][39][40]. Generally, this kind of inhibitor possesses a fully conserved hexapeptide loop region '-RCKAAFC-' and modest trypsin inhibitory activity.…”