Vertebrate TFPI-2 C-terminal peptides exert therapeutic applications against Gram-negative infections
Kasetty, Gopinath LU ; Smeds, Emanuel LU ; Holmberg, Emelie ; Wrange, Louise ; Adikesavan, Selvi and Papareddy, Praveen LU
(2016)
In BMC Microbiology
16(1).
- Abstract
Background: 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. Results: Hydrophobicity and net charge of... (More)
Background: 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. Results: 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. Conclusions: Our results suggest that the evolutionary conserved C-terminal part of TFPI-2 is an interesting agent for the development of novel antimicrobial therapies.
(Less)
- author
- Kasetty, Gopinath
LU
; Smeds, Emanuel
LU
; Holmberg, Emelie
; Wrange, Louise
; Adikesavan, Selvi
and Papareddy, Praveen
LU
- organization
- publishing date
- 2016-06-27
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Antimicrobial, Coagulation, Complement, Evolution, Peptide, Sepsis, TFPI-2, Vertebrates
- in
- BMC Microbiology
- volume
- 16
- issue
- 1
- article number
- 129
- publisher
- BioMed Central (BMC)
- external identifiers
-
- scopus:84976416442
- pmid:27349742
- wos:000378857700003
- ISSN
- 1471-2180
- DOI
- 10.1186/s12866-016-0750-3
- language
- English
- LU publication?
- yes
- id
- fba4b410-5338-4f91-b8d6-8bf9c15cc8e2
- date added to LUP
- 2016-07-21 12:08:28
- date last changed
- 2024-03-22 05:32:19
@article{fba4b410-5338-4f91-b8d6-8bf9c15cc8e2,
abstract = {{<p>Background: 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. Results: 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. Conclusions: Our results suggest that the evolutionary conserved C-terminal part of TFPI-2 is an interesting agent for the development of novel antimicrobial therapies.</p>}},
author = {{Kasetty, Gopinath and Smeds, Emanuel and Holmberg, Emelie and Wrange, Louise and Adikesavan, Selvi and Papareddy, Praveen}},
issn = {{1471-2180}},
keywords = {{Antimicrobial; Coagulation; Complement; Evolution; Peptide; Sepsis; TFPI-2; Vertebrates}},
language = {{eng}},
month = {{06}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{BMC Microbiology}},
title = {{Vertebrate TFPI-2 C-terminal peptides exert therapeutic applications against Gram-negative infections}},
url = {{http://dx.doi.org/10.1186/s12866-016-0750-3}},
doi = {{10.1186/s12866-016-0750-3}},
volume = {{16}},
year = {{2016}},
}