Selective nox-1 inhibitor peptides and uses thereof

Abstract

The present invention relates to novel peptides, compositions and methods for the prevention and/or treatment of pathological conditions and diseases associated with NADPH oxidase 1 (Nox1) activity, and/or increased reactive oxygen species (ROS) production. The novel peptides are thus particularly useful for treating and/or preventing cancer, atherosclerosis, angiogenesis, and aging.

1 - 22 . (canceled) 
     
     
         23 . A method of preventing and/or treating a pathological condition or disease associated with NADPH oxidase 1 (Nox1) activity and/or increased reactive oxygen species (ROS) production in a subject, comprising administering to said subject a therapeutically effective amount of a peptide having 7 to 35 amino acids and comprising the following sequence:
 X1-P-X2-X3-P-X4-R (SEQ ID NO: 1), wherein
 X1 is A, P or Q 
 X2 is P, T, V, A, S, C, M or K 
 X3 is L, I, V or A, and 
 X4 is T, V, S, A or M. 
   
     
     
         24 . The method of  claim 23 , wherein said peptide comprises any of the sequences of PPTVPTR (SEQ ID NO: 2), PPSVPTR (SEQ ID NO: 3), PPMVPTR (SEQ ID NO: 4), PPCVPTR (SEQ ID NO: 5), PPPVPTR (SEQ ID NO: 6), PPAVPTR (SEQ ID NO: 7), PPVVPTR (SEQ ID NO: 8), PPTVPSR (SEQ ID NO: 9), PPTVPMR (SEQ ID NO: 10), PPTVPVR (SEQ ID NO: 11), PPTVPAR (SEQ ID NO: 12), QPTAPTR (SEQ ID NO: 13), PPTLPTR (SEQ ID NO: 14), PPTIPTR (SEQ ID NO: 15), PPTAPTR (SEQ ID NO: 16), PPKVPTR (SEQ ID NO: 17), QPTVPTR (SEQ ID NO: 18), or APTVPTR (SEQ ID NO: 19). 
     
     
         25 . The method of  claim 23  wherein said peptide is conjugated to a cell penetrating peptide or to an agent which increases the accumulation of said peptide in a cell, via a covalent or non-covalent bond, wherein optionally said cell penetrating peptide forms part of the sequence of the peptide. 
     
     
         26 . The method of  claim 25 , wherein said cell penetrating peptide is chosen among a polyarginine tag having the sequence RRRRRRRRR (SEQ ID NO: 46), the NGR peptide derived from the aminopeptidase (CD13) N Ligand (CNGRCG: SEQ ID NO: 47), Antennapedia Leader Peptide (CT) (KKWKMRRNQFWVKVQRG: SEQ ID: 48), Bcl-2 Binding Peptide (Decanoyl-KNLWAAQRYGRELRRMSDEFEGSFKGL: SEQ ID NO: 49), a tat sequence (RKKRRQRRR: SEQ ID NO: 50), the buforin (TRSSRAGLQFPVGRVHRLLRK: SEQ ID NO: 51), a peptidic fragment of the Human T-cell Lymphotrophic Virus (HTLV)-II Rex (TRRQRTRRARRNR: SEQ ID NO: 52), the lipid membrane translocating peptide (KKAAAVLLPVLLAAP: SEQ ID NO: 53), the NRP-1 Targeting Peptide,  Streptomyces hygroscopicus  (RPARPAR: SEQ ID NO: 54), and the penetratin (RQIKIWFQNRRMKWKKGG: SEQ ID NO: 55). 
     
     
         27 . The method of  claim 23  wherein said peptide has the sequence tat-PPTVPTR (SEQ ID NO: 39) or the sequence (R)9-PPTVPTR (SEQ ID NO: 40). 
     
     
         28 . The method of  claim 23 , wherein said pathological condition or disease associated with Nox1 activity and/or increased reactive oxygen species (ROS) production is selected from skin cancer, premalignant skin lesion, squamous cell carcinoma, colon cancer, colon adenocarcinoma, skin cancer caused by xeroderma pigmentosum type C (XPC) gene silencing, skin cancer associated with UV radiation, skin disorders or damages, and/or skin conditions due to UV skin damages and/or aging, skin conditions due to premature aging, and skin tumorigenesis following UV exposition (UV A or UV B). 
     
     
         29 . The method of  claim 23 , wherein NADPH oxidase 1 (Nox1) activity is reduced by at least 20% and/or wherein said peptide selectively decreases and/or inhibits NADPH oxidase 1 (Nox1) activity. 
     
     
         30 . The method of  claim 23 , wherein an effective amount of said peptide is administered or applied to the skin of a subject predisposed or not to the risks of skin cancer due to prolonged UVA and UVB exposure, thereby allowing enhancing protection against UV-radiation or enhancing photo protection to both UVA and UVB rays. 
     
     
         31 . The method of  claim 30 , wherein the peptide repairs and protects the skin, mucous membranes, scalp and/or hair against UV-radiation, UV damage, aging, or any agent that induces stress, inflammation, or skin damage, or wherein the peptide reduces, postpones and/or prevents signs of aging, photo-aging, and skin conditions due to premature aging. 
     
     
         32 . The method of  claim 23 , wherein the levels of reactive oxygen species (ROS) are decreased and/or the production of reactive oxygen species (ROS) is inhibited in a subject, wherein the NADPH oxidase 1 (Nox1) activity is selectively reduced and/or inhibited. 
     
     
         33 . The method of  claim 32 , wherein NADPH oxidase 1 (Nox1) activity is selectively reduced by at least 20%.