MODIFIED PEPTIDE FRAGMENTS OF CAV-1 PROTEIN AND USES THEREOF
Provided herein are compositions comprising modified caveolin-1 (Cav-1) peptides. Further provided are methods of using the modified Cav-1 peptides for the treatment of pulmonary hypertension, lung infections or acute or chronic lung injury, particularly lung fibrosis.
1 . A peptide comprising an amino acid sequence of any one of the sequences listed in Table 1.
2 . The peptide of claim 1 , wherein the peptide comprises at least one N- and/or C-terminal addition lacking identity to SEQ ID NO: 1.
3 . The peptide of claim 1 , wherein the peptide comprises at least one amino acid added to the N-terminus.
4 . The peptide of claim 3 , wherein the at least one amino acid added to the N-terminus lacks identity to the corresponding amino acid in the native Cav-1 sequence.
5 . The peptide of claim 1 , wherein the peptide comprises at least one amino acid added to the C-terminus.
6 . The peptide of claim 5 , wherein the at least one amino acid added to the C-terminus lacks identity to the corresponding amino acid in the native Cav-1 sequence.
7 . The peptide of claim 1 , wherein the peptide comprises at least one amino acid added to the N-terminus and the C-terminus.
8 . The peptide of any of claims 1 - 7 , wherein the peptide comprises L-amino acids.
9 . The peptide of any of claims 1 - 7 , wherein the peptide comprises D-amino acids.
10 . The peptide of any of claims 1 - 7 , wherein the peptide comprises both L- and D-amino acids.
11 . The peptide of any of claims 1 - 7 , wherein the peptide comprises deuterated residues.
12 . The peptide of any of claims 1 - 10 wherein the peptide comprises at least one non-standard amino acid.
13 . The peptide of claim 12 , wherein the peptide comprises at least two non-standard amino acids.
14 . The peptide of claim 12 , wherein the non-standard amino acid is ornithine.
15 . The peptide of any of claims 1 - 14 , wherein the peptide comprises a N-terminal modification.
16 . The peptide of any of claims 1 - 14 , wherein the peptide comprises a C-terminal modification.
17 . The peptide of any of claims 1 - 14 , wherein the peptide comprises a N-terminal modification and a C-terminal modification.
18 . The peptide of claim 15 , wherein the N-terminal modification is acylation.
19 . The peptide of claim 16 , wherein the C-terminal modification is amidation.
20 . The peptide of any one of claims 1 - 19 , further comprising an internalization sequence.
21 . The peptide of claim 20 , wherein the internalization sequence is located at the C-terminal end of the peptide.
22 . The peptide of claim 20 , wherein the internalization sequence is located at the N-terminal end of the peptide.
23 . The peptide of any one of claims 1 - 22 , wherein the peptide further comprises a cap at its N- and/or C-terminus.
24 . The peptide of claim 23 , wherein the peptide comprises the cap at both its N-terminus and C-terminus.
25 . The peptide of any one of claims 1 - 24 , wherein the peptide is cyclized.
26 . The peptide of any one of claims 1 - 25 , wherein the peptide maintains the biological activity of caveolin-1 (Cav-1).
27 . A peptide multimer comprising at least two peptides according to any one of claims 1 - 26 .
28 . The peptide multimer of claim 27 , wherein a first peptide of the at least two peptides is essentially identical to a second peptide of the at least two peptides.
29 . The peptide multimer of claim 27 , wherein a first peptide of the at least two peptides is not identical to a second peptide of the at least two peptides.
30 . A composition comprising a peptide of any one of claims 1 - 29 .
31 . The composition of claim 30 , wherein the peptide is substantially pure.
32 . The composition of claim 30 or 31 , wherein the peptide is at least 95% pure.
33 . The composition of any one of claims 30 - 32 , wherein the peptide is at least 98% pure.
34 . A pharmaceutical composition comprising a peptide of any one of claims 1 - 29 and a pharmaceutically acceptable carrier.
35 . The pharmaceutical composition of claim 34 , wherein the pharmaceutical composition is formulated for oral, intranasal, intrabronchial, intravenous, intraarticular, parenteral, enteral, topical, subcutaneous, intramuscular, buccal, sublingual, rectal, intravaginal, intrapenile, intraocular, epidural, intracranial, or inhalational administration.
36 . The pharmaceutical composition of claim 34 , wherein the pharmaceutical composition is formulated for lung instillation.
37 . The pharmaceutical composition of claim 34 , wherein the pharmaceutical composition is formulated as a nebulized solution.
38 . A polynucleotide comprising a nucleic acid sequence encoding the peptide of any one of claims 1 - 29 .
39 . A method of treating or preventing a disease or condition in a subject comprising administering to the subject an effective amount of a peptide of any of claims 1 - 29 .
40 . The method of claim 39 , wherein the subject has a disease or condition characterized by fibrosis.
41 . The method of claim 39 , wherein the subject has a fibrotic or inflammatory disease.
42 . The method of claim 41 , wherein the subject has organ fibrosis.
43 . The method of claim 42 , wherein the subject has kidney, liver, lung or heart fibrosis.
44 . The method of claim 42 , wherein the fibrosis is pulmonary fibrosis.
45 . The method of claim 42 , wherein the fibrosis is idiopathic pulmonary fibrosis.
46 . The method of claim 39 , wherein the subject has pulmonary hypertension
47 . The method of claim 46 , wherein the pulmonary hypertension is Group 1 pulmonary hypertension.
48 . The method of claim 46 , wherein the pulmonary hypertension is Group 2 pulmonary hypertension.
49 . The method of claim 46 , wherein the pulmonary hypertension is Group 3 pulmonary hypertension.
50 . The method of claim 46 , wherein the pulmonary hypertension is Group 4 pulmonary hypertension.
51 . The method of claim 46 , wherein the pulmonary hypertension is Group 5 pulmonary hypertension.
52 . The method of claim 46 , wherein the subject has pulmonary arterial hypertension.
53 . The method of claim 52 , wherein the pulmonary arterial hypertension is primary pulmonary hypertension.
54 . The method of claim 52 , wherein the subject has a mean pulmonary artery pressure greater than 19 mm Hg.
55 . The method of claim 39 , wherein the inflammatory disease is an inflammatory eye disease.
56 . The method of claim 39 , further defined as a method of treating or preventing pulmonary inflammation, acute lung injury, lung infection or lung disease in a subject.
57 . The method of claim 56 , wherein the subject has pulmonary inflammation.
58 . The method of claim 56 , wherein the subject has chronic obstructive pulmonary disorder (COPD).
59 . The method of claim 39 , wherein the subject is undergoing chemotherapy or radiation therapy.
60 . The method of claim 56 , wherein the subject has an acute lung injury.
61 . The method of claim 56 , wherein the subject has a lung infection.
62 . The method of claim 56 , wherein the subject has a chemical-induced lung injury.
63 . The method of claim 56 , wherein the subject has plastic bronchitis.
64 . The method of claim 56 , wherein the subject has asthma.
65 . The method of claim 56 , wherein the subject has acute respiratory distress syndrome (ARDS).
66 . The method of claim 56 , wherein the subject has inhalational smoke induced acute lung injury (ISALI).
67 . The method of claim 56 , wherein the subject has bronchiolitis.
68 . The method of claim 56 , wherein the subject has bronchiolitis obliterans.
69 . The method of claim 56 , wherein the lung disease is a fibrotic condition of the lungs.
70 . The method of claim 56 , wherein the lung disease is interstitial lung disease.
71 . The method of claim 56 , wherein the lung disease is Idiopathic Pulmonary Fibrosis (IPF) or lung scarring.
72 . The method of claim 56 , wherein the administering comprises nebulizing a solution comprising the variant polypeptide.
73 . The method of claim 39 , wherein the peptide is administered systemically.
74 . The method of claim 39 , wherein the peptide is administered intranasally, intrabronchially, or by instillation into lungs of the subject.
75 . The method of claim 39 , wherein the peptide is administered locally to diseased tissue.
76 . The method of claim 39 , further comprising administering at least one additional anti-fibrotic therapeutic.
77 . The method of claim 76 , wherein the at least one additional anti-fibrotic is NSAID, steroid, DMARD, immunosuppressive, biologic response modulators, or bronchodilator.
78 . The method of claim 39 , wherein the subject is a human.
79 . A peptide comprising an amino acid sequence that shares at least 95% sequence identity to any one of SEQ ID NOs: 1-111.
80 . A peptide comprising an amino acid sequence of any one of SEQ ID NOs: 1-111.
81 . A pharmaceutical composition comprising the peptide of claim 79 or 80 .
82 . A method of treating or preventing a disease or condition in a subject comprising administering to the subject an effective amount of the peptide of claim 79 or 80 or the pharmaceutical composition of claim 81 .