title: Vertebrate TFPI-2 C-terminal peptides exert therapeutic applications against Gram-negative infections.
abstract: Tissue factor pathway inhibitor-2 (TFPI-2) is a serine protease inhibitor that exerts multiple physiological and patho-physiological activities involving the modulation of coagulation, angiogenesis, tumor invasion, and apoptosis. In previous studies we reported a novel role of human TFPI-2 in innate immunity by serving as a precursor for host defense peptides. Here we employed a number of TFPI-2 derived peptides from different vertebrate species and found that their antibacterial activity is evolutionary conserved although the amino acid sequence is not well conserved. We further studied the theraputic potential of one selected TFPI-2 derived peptide (mouse) in a murine sepsis model.
  
  
  
  Hydrophobicity and net charge of many peptides play a important role in their host defence to invading bacterial pathogens. In vertebrates, the C-terminal portion of TFPI-2 consists of a highly conserved cluster of positively charged amino acids which may point to an antimicrobial activity. Thus a number of selected C-terminal TFPI-2 derived peptides from different species were synthesized and it was found that all of them exert antimicrobial activity against E. coli and P. aeruginosa. The peptide-mediated killing of E. coli was enhanced in human plasma, suggesting an involvement of the classical pathway of the complement. Under in vitro conditions the peptides displayed anti-coagulant activity by modulating the intrinsic pathway of coagulation and in vivo treatment with the mouse derived VKG24 peptide protects mice from an otherwise lethal LPS shock model.
  
  
  
  Our results suggest that the evolutionary conserved C-terminal part of TFPI-2 is an interesting agent for the development of novel antimicrobial therapies.
authors.affiliation: Division of Respiratory Medicine and Allergology, Lund University, Lund, Sweden.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Kasetty
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, B14, Tornavägen 10, SE-221 84, Lund, Sweden.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Smeds
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, B14, Tornavägen 10, SE-221 84, Lund, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Holmberg
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, B14, Tornavägen 10, SE-221 84, Lund, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Wrange
authors.affiliation: School of Biosciences and Technology, Environmental Division, VIT University, Tamil Nadu, India.|Dept of Biotechnology, DKM college for Women, Sainathapuram, 632001, Vellore, India.
authors.forename: Selvi
authors.initials: S
authors.lastname: Adikesavan
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Lund University, Biomedical Center, B14, Tornavägen 10, SE-221 84, Lund, Sweden. praveen.papareddy@med.lu.se.
authors.forename: Praveen
authors.identifier: 0000-0002-3872-478X
authors.initials: P
authors.lastname: Papareddy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000472:pathogenicity; D001777:Blood Coagulation / Q000187:drug effects; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006461:Hemolysis; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050296:Microbial Viability / Q000187:drug effects; D010455:Peptides / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D010802:Phylogeny; D010949:Plasma; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy; D016415:Sequence Alignment; D017385:Sequence Homology; D013045:Species Specificity; D014714:Vertebrates / Q000145:classification / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D016207:Cytokines; D006023:Glycoproteins; D010455:Peptides; C021240:tissue-factor-pathway inhibitor 2
keywords: Antimicrobial; Coagulation; Complement; Evolution; Peptide; Sepsis; TFPI-2; Vertebrates