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Ep 2245149 B1 (19) TZZ __T (11) EP 2 245 149 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 9/64 (2006.01) A61K 38/48 (2006.01) 14.10.2015 Bulletin 2015/42 (86) International application number: (21) Application number: 09704223.8 PCT/IB2009/050237 (22) Date of filing: 22.01.2009 (87) International publication number: WO 2009/093189 (30.07.2009 Gazette 2009/31) (54) PEPTIDES, COMPOSITIONS, AND USES THEREOF PEPTIDE, ZUSAMMENSETZUNGEN UND VERWENDUNGEN DAVON PEPTIDES, COMPOSITIONS, ET LEURS UTILISATIONS (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A1-2006/021062 WO-A1-2007/028223 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR • REIS CLEYSON VALENCA ET AL: "Lopap, a prothrombin activator from Lonomia obliqua (30) Priority: 22.01.2008 US 22747 P belonging to the lipocalin family: recombinant production, biochemical characterization and (43) Date of publication of application: structure-function insights" BIOCHEMICAL 03.11.2010 Bulletin 2010/44 JOURNAL, vol. 398, no. Part 2, September 2006 (2006-09), pages 295-302, XP002535567 ISSN: (73) Proprietors: 0264-6021-& DATABASEUniProt [Online] 24 July • Fundação de Amparo à Pesquisa do Estado de 2007 (2007-07-24), "RecName: Full=Lopap; São EC=<A HREF="http://srs.ebi.ac.uk/srsbin/cgi- Paulo - FAPESP bin/ wgetz?[enzyme-ECNumber:3.4.21.*]+- 05468-901 São Paulo (BR) e">3.4.2 1.-</A>; AltName: Full=Prothrombin • Biolab Sanus Farmacéutica Ltda activator; AltName: Full=Lipocalin-1/4; Flags: 06767-220 Taboä da Serra - SP (BR) Precursor;" XP002535537 retrieved from EBI • Chudzinski-Tavassi, Ana Marisa accession no. UNIPROT:Q5ECE3 Database CEP-05503-900 Sao Paulo, SP (BR) accession no. Q5ECE3 • RICCI-SILVA M E ET AL: "Immunochemical and (72) Inventors: proteomic technologies as tools for unravelling • CHUDZINSKI-TAVASSI, Ana Marisa toxins involved in envenoming by accidental CEP-05503-900 Sao Paulo, SP (BR) contact with Lonomia obliqua caterpillars", • DE SOUZA VENTURA, Janaina TOXICON, ELMSFORD, NY, US, vol. 51, no. 6, 1 CEP-05503-900 Sao Paulo, SP (BR) May 2008 (2008-05-01), pages 1017-1028, • CARRIJO CARVALHO, Linda Christian XP022620485, ISSN: 0041-0101, DOI: CEP-05503-900 Sao Paulo, SP (BR) 10.1016/J.TOXICON.2008.01.013 [retrieved on 2008-02-03] (74) Representative: Herzog, Fiesser & Partner Patentanwälte PartG mbB Isartorplatz 1 80331 München (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 245 149 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 245 149 B1 Description [0001] This application claims the benefit of the filing date of U.S. provisional application No. 61/022,747, which was filed on January 22, 2008. 5 BACKGROUND OF THE INVENTION [0002] The Lopap protein is a venom protease from the caterpillar Lonomia obiqua, which has several biological activities, including increasing cell viability, and induction of nitric oxide, and proteins of the extracellular matrix (ECM) 10 (WO2007/028223 and Ricci-Silva et al., Toxicon 51:1017-1028 (2008)). [0003] The extracellular matrix (ECM) is a complex structural entity that surrounds and supports cells within living systems. In mammalian tissues the ECM is most commonly found in connective tissues such as tendon, cartilage, bone or dermis of the skin. [0004] The ECM guides the generation of tissue and the repair of wounds, and several medical conditions are attributed 15 to defectively-made ECM (e.g., scurvy); continually-degraded ECM (e.g., periodontal disease, non-healing ulcers); or deteriorating ECM or decreased ECM production (e.g., aged tissue). The importance of the ECM has prompted devel- opment of EMC-supplying therapies for use in tissue generation, wound repair, disease and aging treatments, and cosmetic uses. 20 SUMMARY OF THE INVENTION [0005] The present invention features peptides that share homology with a region of the Lopap protein. The peptides are capable of stimulating production of extracellular matrix (ECM) proteins in cells ( e.g., fibroblasts), and hence can be utilized as a generating agent for tissue and skin_as well as utilized as a cosmetic. 25 [0006] In some embodiments, the peptide stimulates production of ECM proteins (e.g., fibronectin, tenascin, collagen, procollagen, or a combination thereof). [0007] In some aspects, the disclosure provides an isolated peptide that is substantially homologous to SEQ ID NO:1. [0008] In another aspect, the disclosure provides a cosmetic composition that includes a peptide described herein (e.g., in combination with one or more cosmetically-acceptable excipients). 30 [0009] In another aspect, the disclosure provides a pharmaceutical composition that includes a peptide described herein (e.g., in combination with one or more pharmaceutically-acceptable excipients). [0010] While the invention is described further below, we note here that the invention encompasses isolated peptides that consist of or that comprise an amino acid sequence that is at least 70% identical to ( e.g., at least 75%, 80%, 85%, 90%, 95% or 100% identical) the amino acid sequence YAIGYSCKDYK (SEQ ID NO:1). Such peptides can also stimulate 35 production of one or more ECM proteins in cells ( e.g., within fibroblast cells). [0011] The isolated peptide can consist of or comprise an amino acid sequence that differs from a reference sequence (e.g., SEQ ID NO:1) by virtue of including one or more amino acid substitutions, additions, or deletions. For example, the isolated peptide can differ from a peptide represented by SEQ ID NO:1 by up to six amino acid substitutions, additions, and/or deletions and be capable of stimulating production of one or more ECM proteins in fibroblast cells. 40 [0012] The invention further encompasses pharmaceutical compositions that include a peptide described herein. The pharmaceutical composition can include a pharmaceutically acceptable carrier ( e.g., a water-based diluent) and can be in the form of a liquid or an ointment. The pharmaceutical compositions can further include a wound healing agent. The pharmaceutical composition can be formulated for oral, intramuscular, intravenous, subcutaneous, topical, pulmonary, intranasal, buccal, rectal, sublingual, intradermal, intraperitoneal or intrathecal use. 45 [0013] The methods of the invention encompass methods of reducing cell death and/or tissue degeneration in a subject by administering one or more of the pharmaceutical compositions described herein to the cells of the subject e.g.,( a human patient). The subject may have been identified as experiencing cell death and/or tissue generation caused, for example, by disease, trauma, or aging. The methods can further include administering a wound healing agent. [0014] The methods of the invention encompass methods of wound healing and/or regenerating tissue in a subject 50 by administering one or more of the pharmaceutical compositions described herein to the subject ( e.g., a human patient). The methods can further include a step of identifying a patient in need of treatment and, optionally, further administering a wound healing agent. [0015] Any of the compositions can be administered in a therapeutically effective amount. [0016] Also within the scope of the present invention is the use of an isolated peptide as described herein in the 55 preparation of a medicament. The medicament can be for reducing cell death and/or tissue degeneration or for wound healing and/or regenerating tissue. 2 EP 2 245 149 B1 BRIEF DESCRIPTION OF THE DRAWINGS [0017] 5 Figure 1 is a bar graph showing the influence of four peptides on the viability of cells tested by MTT (3-[4,5-dimeth- ylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). Figure 2 is a line graph showing the influence of peptide CNF011.05B on the viability, tested by MTT, of endothelial cells incubated for 120 hours in medium supplemented with 1% FBS. Figure 3 is a line graph showing the influence of peptide CNF011.05D on the viability, tested by MTT, of endothelial 10 cells incubated for 120 hours in medium supplemented with 1% FBS. Figure 4 is a bar graph showing the influence of peptide CNF011.05D plus L-NAME on the viability, tested by flow cytometry, ofneutrophils incubated in medium supplemented with 1% FBS. Figure 5 is a bar graph showing the influence of peptide CNF011.05D plus L-NAME on the viability, tested by flow cytometry, of primary endothelial cells incubated in medium supplemented with 1% FBS. 15 Figure 6 is a bar graph showing the influence of peptide CNF011.05D plus L-NAME on NO 2 production by neurophils as measured by use of the Griess reaction. Figure 7 is a plot illustrating the percent of fibroblasts producing fibronectin upon incubation with peptide CNF011.05D at 0.35 mg and 5 mg. Figure 8 is a plot illustrating the percent of fibroblasts producing tenascin upon incubation with peptide CNF011.05D 20 at 0.35 mg and 5 mg. Figure 9 is a plot illustrating the percent of fibroblasts producing procollagen upon incubation with peptide CNF011.05D at 0.35 mg and 5 mg. DETAILED DESCRIPTION OF THE INVENTION 25 [0018] The present disclosure features novel peptides that are useful for stimulating production of ECM proteins, particularly fibronectin, tenascin, collagen, and procollagen. Described herein are methods of using such peptides, methods of making such peptides, and kits and compositions containing such peptides. [0019] The peptides may be used to generate extracellular matrix proteins, particularly fibronectin, tenascin, collagen, 30 and procollagen.
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