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 β-hairpin 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.

Department of Biochemistry Cardiovascular Research Institute Maastricht Maastricht University 6229 ER Maastricht The Netherlands

Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical Sciences Southern Medical University Guangzhou 510515 China

Institute of Molecular Biology and Biotechnology Foundation for Research and Technology Hellas N Plastira 100 70013 Heracklion Crete Greece

Institute of Parasitology Biology Center of the Czech Academy of Sciences Branisovska 31 Budweis 37005 Czech Republic

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