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Novel antimicrobial peptides with heparin binding activity

a technology of antimicrobial peptides and heparin, which is applied in the direction of peptide/protein ingredients, peptide sources, applications, etc., can solve the problems of not always the best treatment option for vaccines, no vaccine is available, and localised or generalised acute infections, so as to reduce the risk of allergenic reactions to antimicrobial peptides, reduce production costs, and increase the stability of peptides

Inactive Publication Date: 2007-08-09
DERMAGEN AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019] The antimicrobial peptides and the corresponding antimicrobial / pharmaceutical compositions according to the invention provide peptides and compositions, which facilitate efficient prevention, reduction or elimination of microorganisms. Thereby the possibility to combat microorganisms, which are resistant or tolerant against the antibiotic agents, may be increased. Moreover, mammals, which are allergenic against commercially available antimicrobial agents, may be treated. By providing antimicrobial / pharmaceutical compositions, which are derived from endogenous proteins, the probability may be reduced or even eliminated that a mammal will develop allergy against these particular peptides. This makes the antimicrobial / pharmaceutical compositions useful for several applications in which the antimicrobial / pharmaceutical compositions contact a mammal either as a medicament or as an additive to prevent infections.
[0020] Additionally, the use of short peptides improves bioavailibility. Furthermore, the use of structurally distinct heparin-binding antimicrobial peptides with specific or preferable actions on Gram-negative and Gram-positive bacteria, or fungi, enables specific targeting of various microorganisms, thus minimising development of resistance and ecological problems. By supplementing peptides that already exist in the mammal, the risk of additional ecological pressure by novel antibiotics is further diminished. Finally, these formulations may also enhance the effect of endogenous antimicrobial peptides.

Problems solved by technology

However, in some instances, bacteria, fungi, or viruses are not always cleared, which may cause localised or generalised acute infections.
This is a serious concern at perinatal-, burn, or intensive care units, and in immunocompromised individuals.
However, vaccines are not always the best treatment option and for certain microorganisms no vaccine is available.
Most likely, resistance problems will increase in the near future.
Additionally, several individuals have developed allergy against the antibiotic agent, thereby reducing the possibility to effectively use certain antibiotic agents.

Method used

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  • Novel antimicrobial peptides with heparin binding activity
  • Novel antimicrobial peptides with heparin binding activity
  • Novel antimicrobial peptides with heparin binding activity

Examples

Experimental program
Comparison scheme
Effect test

example 1

Antimicrobial Peptides

[0093] The antimicrobial peptides shown in the sequence listing and Table 1 below were synthesized by Innovagen AB, Ideon, SE-22370, Lund, Sweden. The purity and molecular weight of these peptides was confirmed by mass spectral analysis (MALDI.TOF Voyager).

TABLE 1OriginPeptideCodeC3aLRKCCEDGMR ENPMRFSCQR RTRFISLRK26C3aLGEACKKVFL DCCNYITELR RQHARASLGE27C3aCNYITELRRQHARASHLGLARCNY21Laminin-α1SRNLSEIKLLISQARKSRN16Laminin-α1SRNLSEIKLL ISQARKQAAS IKVAVSADRSRN29Laminin-α1KDFLSIELFR GRVKVKDF15Laminin-α1SAVRKKLSVE LSIRTSAV15Laminin-α5LGTRLRAQSR QRSRPGRWHK VSVRWLGT25Laminin-α5PPPPLTSASK AIQVFLLGGS RKRVLPPP25Laminin-α5RLRAQSRQRS RPGRWHKVSV RWRLR22Laminin-α1PGRWHKVSVR WPGR11Laminin-β1RIQNLLKITNLRIKFVKLRIQ18FibronectinQPPRARITGY IIKYEKPGQPP18Von Willebrand FactorYIGLKDRKRP SELRRIASQV KYAYIG23VitronectinAKKQRFRHRN RKGYRAKK15Protein C inhibitorSEKTLRKWLK MFKKRQLELYSEK20Histidine-rich glycopro-GHHPHGHHPH GHHPHGHHPHGHH20teinKininogenKHNLGHGHKH ERDQGHGHQRKHN20KininogenGGHVL...

example 2

Antibacterial Effects of Arginine and Lysine-Rich Peptides

[0094]FIG. 1 describes bactericidal effects of arginine and lysine-rich peptides (Sequence listing) on Enterococcus faecalis. Bacteria were grown to mid-logarithmic phase in Todd-Hewitt (TH) medium. Bacteria were washed and diluted in either 10 mM Tris, pH 7.4, containing 5 mM glucose Bacteria (50 μl; 2×106 cfu / ml) were incubated, at 37° C. for 2 hours, with the synthetic peptide at concentrations ranging from 0.03 to 60 μM. To quantify the bactericidal activity, serial dilutions of the incubation mixture were plated on TH agar, followed by incubation at 37° C. overnight and the number of colony-forming units was determined.

[0095] 2×106 colony-forming units (CFU)×ml−1 of E. faecalis (isolate 2374) were incubated in 50 μl with peptides at concentrations ranging from 0.03 to 60 μM. (A) Synthetic peptides derived from laminin. Effect of peptides from the LG-domain of the α5 chain (PPP25: SEQ ID NO:13, LGT25: SEQ ID NO:12, RLR...

example 3

Radial Diffusion Assay Analysis of Antimicrobial Peptides (Table 2)

[0096] Radial diffusion assays (RDA) were performed essentially as described earlier (Andersson et al., Eur J Biochem, 2004, 271:1219-1226). Briefly, bacteria (E. coli) or fungi (C. albicans) were grown to mid-logarithmic phase in 10 ml of full-strength (3% w / v) trypticase soy broth (TSB) (Becton-Dickinson, Cockeysville, Md.). The microorganisms were washed once with 10 mM Tris, pH 7.4. 4×106 bacterial cfu or 1×105 fungal cfu was added to 5 ml of the underlay agarose gel, consisting of 0.03% (w / v) TSB, 1% (w / v) low-electroendosmosistype (Low-EEO) agarose (Sigma, St Louise Mo.) and a final concentration of 0.02% (v / v) Tween 20 (Sigma). The underlay was poured into a Ø85 mm petri dish. After agarose solidified, 4 mm-diameter wells were punched and 6 μl of test sample was added to each well. Plates were incubated at 37° C. for 3 hours to allow diffusion of the peptides. The underlay gel was then covered with 5 ml of m...

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Abstract

The invention relates to an antimicrobial peptide with heparin binding activity, being derived from endogenous mammalian proteins being substantially free from antimicrobial activity selected from the group consisting of laminin isoforms, complement factor C3, histidin rich glycoprotein and kininogen and having from 10 to 36 amino acid residues, wherein the antimicrobial peptide consists of at least four amino acid residues selected from the group consisting of K, R and H. The invention also relates to pharmaceutical compositions comprising said antimicrobial peptide and use of the antimicrobial peptide and / or antimicrobial / pharmaceutical composition.

Description

FIELD OF INVENTION [0001] The invention relates to antimicrobial peptides with heparin binding activity, being derived from endogenous mammalian proteins being substantially free from antimicrobial activity selected from the group consisting of laminin isoforms, complement factor C3, histidin rich glycoprotein and kininogen and having from 10 to 36 amino acid residues, wherein the antimicrobial peptides consists of at least four amino acid residues selected from the group consisting of K, R and H. The invention also relates to pharmaceutical compositions comprising said antimicrobial peptides and use of the antimicrobial peptides and / or antimicrobial / pharmaceutical compositions. BACKGROUND OF INVENTION [0002] Several infections are successfully combated by the immune system of a mammal such as a human being. However, in some instances, bacteria, fungi, or viruses are not always cleared, which may cause localised or generalised acute infections. This is a serious concern at perinatal...

Claims

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Application Information

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IPC IPC(8): A61K38/16C07K14/195A61K38/00C07KC07K14/47C07K14/81
CPCA61K38/1709A61K38/39C07K14/8128C07K14/4723A61K38/57A61P31/00A61P31/04A61P31/10A61P31/12A61P33/14Y02A50/30C07K14/47
Inventor SCHMIDTCHEN, ARTURMALMSTEN, MARTIN
Owner DERMAGEN AB
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