SARomics AB

Lund, Sweden

SARomics AB

Lund, Sweden
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Papareddy P.,Lund University | Rydengard V.,Lund University | Pasupuleti M.,Lund University | Walse B.,SARomics AB | And 5 more authors.
PLoS Pathogens | Year: 2010

The coagulation system is characterized by the sequential and highly localized activation of a series of serine proteases, culminating in the conversion of fibrinogen into fibrin, and formation of a fibrin clot. Here we show that C-terminal peptides of thrombin, a key enzyme in the coagulation cascade, constitute a novel class of host defense peptides, released upon proteolysis of thrombin in vitro, and detected in human wounds in vivo. Under physiological conditions, these peptides exert antimicrobial effects against Gram-positive and Gram-negative bacteria, mediated by membrane lysis, as well as immunomodulatory functions, by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, they are protective against P. aeruginosa sepsis, as well as lipopolysaccharide-induced shock. Moreover, the thrombin-derived peptides exhibit helical structures upon binding to lipopolysaccharide and can also permeabilize liposomes, features typical of "classical" helical antimicrobial peptides. These findings provide a novel link between the coagulation system and hostdefense peptides, two fundamental biological systems activated in response to injury and microbial invasion. © 2010 Papareddy et al.

Papareddy P.,Lund University | Morgelin M.,Lund University | Walse B.,SARomics AB | Schmidtchen A.,Lund University | Malmsten M.,Uppsala University
Journal of Peptide Science | Year: 2012

Antimicrobial peptides are important effector molecules of the innate immune system. Here, we describe that peptides derived from the heparin-binding disulfide-constrained loop region of human ß-amyloid precursor protein are antimicrobial. The peptides investigated were linear and cyclic forms of NWCKRGRKQCKTHPH (NWC15) as well as the cyclic form comprising the C-terminal hydrophobic amino acid extension FVIPY (NWCKRGRKQCKTHPHFVIPY; NWC20c). Compared with the benchmark antimicrobial peptide LL-37, these peptides efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Staphylococcus aureus and Bacillus subtilis, and the fungi Candida albicans and Candida parapsilosis. Correspondingly, fluorescence and electron microscopy demonstrated that the peptides caused defects in bacterial membranes. Analogously, the peptides permeabilised negatively charged liposomes. Despite their bactericidal effect, the peptides displayed very limited hemolytic activities within the concentration range investigated and exerted very small membrane permeabilising effects on human epithelial cells. The efficiency of the peptides with respect to bacterial killing and liposome membrane leakage was in the order NWC20c>NWC15c>NWC15l, which also correlated to the adsorption density for these peptides at the model lipid membrane. Thus, whereas the cationic sequence is a minimum determinant for antimicrobial action, a constrained loop-structure as well as a hydrophobic extension further contributes to membrane permeabilising activity of this region of amyloid precursor protein. © 2012 European Peptide Society and John Wiley & Sons, Ltd.

Fritzson I.,Active Biotech Research AB | Svensson B.,SARomics AB | Al-Karadaghi S.,Lund University | Walse B.,SARomics AB | And 4 more authors.
ChemMedChem | Year: 2010

A strategy that combines virtual screening and structureguided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl) anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure-activity relationships upon expansion. The novel N-(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented. © 2010 Wiley-VCH Verlag GmbHand Co. KGaA, Weinheim.

Kasetty G.,Lund University | Papareddy P.,Lund University | Kalle M.,Lund University | Rydengrd V.,Lund University | And 5 more authors.
Journal of Innate Immunity | Year: 2011

Serine proteases of the S1 family have maintained a common structure over an evolutionary span of more than one billion years, and evolved a variety of substrate specificities and diverse biological roles, involving digestion and degradation, blood clotting, fibrinolysis and epithelial homeostasis. We here show that a wide range of C-terminal peptide sequences of serine proteases, particularly from the coagulation and kallikrein systems, share characteristics common with classical antimicrobial peptides of innate immunity. Under physiological conditions, these peptides exert antimicrobial effects as well as immunomodulatory functions by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, selected peptides are protective against lipopolysaccharide-induced shock. Moreover, these S1-derived host defense peptides exhibit helical structures upon binding to lipopolysaccharide and also permeabilize liposomes. The results uncover new and fundamental aspects on host defense functions of serine proteases present particularly in blood and epithelia, and provide tools for the identification of host defense molecules of therapeutic interest. © 2011 S. Karger AG, Basel.

Svensson S.L.,Lund University | Pasupuleti M.,Lund University | Walse B.,SARomics AB | Malmsten M.,Uppsala University | And 7 more authors.
Journal of Biological Chemistry | Year: 2010

Antibacterial peptides of the innate immune system combat pathogenic microbes, but often have additional roles in promoting inflammation and as growth factors during tissue repair. Midkine (MK) and pleiotrophin (PTN) are the only two members of a family of heparin-binding growth factors. They show restricted expression during embryogenesis and are up-regulated in neoplasia. In addition, MK shows constitutive and inflammation-dependent expression in some non-transformed tissues of the adult. In the present study, we show that both MK and PTN display strong antibacterial activity, present at physiological salt concentrations. Electron microscopy of bacteria and experiments using artificial lipid bilayers suggest that MK andPTNexert their antibacterial action via a membrane disruption mechanism. The predicted structure of PTN, employing the previously solved MK structure as a template, indicates that both molecules consist of two domains, each containing three antiparallel β-sheets. The antibacterial activity was mapped to the unordered C-terminal tails of both molecules and the last β-sheets of the N-terminals. Analysis of the highly conserved MK and PTN orthologues from the amphibian Xenopus laevis and the fish Danio rerio suggests that they also harbor antibacterial activity in the corresponding domains. In support of an evolutionary conserved function it was found that the more distant orthologue, insect Miple2 from Drosophila melanogaster, also displays strong antibacterial activity. Taken together, the findings suggest that MK and PTN, in addition to their earlier described activities, may have previously unrealized important roles as innate antibiotics. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

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