title: Beneficial effects of trypsin inhibitors derived from a spider venom peptide in L-arginine-induced severe acute pancreatitis in mice.
abstract: HWTI is a 55-residue protein isolated from the venom of the spider Ornithoctonus huwena. It is a potent trypsin inhibitor and a moderate voltage-gated potassium channel blocker. Here, we designed and expressed two HWTI mutants, HWTI-mut1 and HWTI-mut2, in which the potassium channel inhibitory activity was reduced while the trypsin inhibitory activity of the wild type form (approximately 5 EPU/mg) was retained. Animal studies showed that these mutants were less toxic than HWTI. The effects of HWTI and HWTI-mut1 were examined in a mouse model of acute pancreatitis induced by intraperitoneal injection of a large dose of L-arginine (4 mg/kg, twice). Serum amylase and serum lipase activities were assessed, and pathological sections of the pancreas were examined. Treatment with HWTI and HWTI-mut1 significantly reduced serum amylase and lipase levels in a dose dependent manner. Compared with the control group, at 4 mg/kg, HWTI significantly reduced serum amylase level by 47% and serum lipase level by 73%, while HWTI-mut1 significantly reduced serum amylase level by 59% and serum lipase level by 72%. Moreover, HWTI and HWTI-mut1 effectively protected the pancreas from acinar cell damage and inflammatory cell infiltration. The trypsin inhibitory potency and lower neurotoxicity of HWTI-mut1 suggest that it could potentially be developed as a drug for the treatment of acute pancreatitis with few side effects.
authors.affiliation: College of Life Sciences, Hunan Normal University, Changsha, Hunan, China.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Ning
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Hengyun
authors.initials: H
authors.lastname: Wang
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.forename: Huaxin
authors.initials: H
authors.lastname: Tang
authors.forename: Songping
authors.initials: S
authors.lastname: Liang
authors.forename: Xiaoliu
authors.initials: X
authors.lastname: Shi
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D005260:Female; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010195:Pancreatitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D013111:Spider Venoms / Q000737:chemistry*; D014357:Trypsin / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019476:Insect Proteins; D010446:Peptide Fragments; D015221:Potassium Channels; D013111:Spider Venoms; D014361:Trypsin Inhibitors; D001120:Arginine; D014357:Trypsin