MODIFIED CAVEOLIN-1 PEPTIDES FOR THE TREATMENT OF PATHOGEN-INDUCED LUNG INJURY
Provided herein are methods of using modified caveolin-1 (Cav-1) peptides to treat or prevent pathogen-induced lung injury and disrepair. In particular, provided are methods of using the modified Cav-1 peptides for the treatment of pathogen-induced lung injury and disrepair caused by a coronavirus, such as, for example, SARS-CoV-2.
1 . A method of treating or preventing pathogen-induced lung injury in a subject comprising administering to the subject a therapeutically effective amount of a modified Cav-1 peptide:
(i) consisting of any one of the amino acid sequences of SEQ ID NOs: 4-20; or
(ii) comprising any one of the amino acid sequences of SEQ ID NOs: 4-20 with one or more amino acid substitutions, insertions, deletions, or modifications.
2 . The method of claim 1 , wherein the pathogen-induced lung injury is caused by a viral infection, a bacterial infection, or a fungal infection.
3 . The method of claim 2 , wherein the viral infection is a coronavirus infection.
4 . The method of claim 3 , wherein the coronavirus is MERS-CoV, SARS-CoV-1, or SARS-CoV-2.
5 . The method of claim 4 , wherein the coronavirus is MERS-CoV.
6 . The method of claim 5 , wherein the subject has Middle East respiratory syndrome (MERS).
7 . The method of claim 4 , wherein the coronavirus is SARS-CoV-1.
8 . The method of claim 7 , wherein the subject has severe acute respiratory syndrome (SARS).
9 . The method of claim 4 , wherein the coronavirus is SARS-CoV-2.
10 . The method of claim 9 , wherein the subject has coronavirus disease 2019 (COVID-19).
11 . The method of claim 2 , wherein the pathogen-induced lung injury is caused by a double-stranded DNA (dsDNA) virus, a single-stranded DNA (ssDNA) virus, a single-stranded RNA (ssRNA) virus, or a double-stranded RNA (dsRNA) virus.
12 . The method of claim 11 , wherein the ssRNA virus is a positive-sense ssRNA virus (+ssRNA).
13 . The method of claim 11 , wherein the ssRNA virus is a negative-sense ssRNA virus (−ssRNA).
14 . The method of claim 1 , wherein the modified Cav-1 peptide comprises L-amino acids.
15 . The method of claim 1 , wherein the modified Cav-1 peptide comprises D-amino acids.
16 . The method of claim 1 , wherein the modified Cav-1 peptide comprises both L- and D-amino acids.
17 . The method of claim 1 , wherein the modified Cav-1 peptide comprises deuterated residues.
18 . The method of claim 1 wherein the modified Cav-1 peptide comprises at least one non-standard amino acid.
19 . The method of claim 18 , wherein the modified Cav-1 peptide comprises at least two non-standard amino acids.
20 . The method of claim 18 , wherein the non-standard amino acid is ornithine.
21 . The method of claim 1 , wherein the modified Cav-1 peptide comprises a N-terminal modification.
22 . The method of claim 1 , wherein the modified Cav-1 peptide comprises a C-terminal modification.
23 . The method of claim 1 , wherein the modified Cav-1 peptide comprises a N-terminal modification and a C-terminal modification.
24 . The method of claim 21 , wherein the N-terminal modification is acylation.
25 . The method of claim 22 , wherein the C-terminal modification is amidation.
26 . The method of claim 1 , wherein the modified Cav-1 peptide comprises the amino acid sequence of KASFTTFTVTKGS (SEQ ID NO: 4).
27 . The method of claim 1 , wherein the modified Cav-1 peptide comprises the amino acid sequence of KASFTTFTVTKGS-NH2 (SEQ ID NO: 5).
28 . The method of claim 1 , wherein the modified Cav-1 peptide comprises the amino acid sequence of aaEGKASFTTFTVTKGSaa (SEQ ID NO: 6).
29 . The method of claim 1 , wherein the modified Cav-1 peptide comprises the amino acid sequence of aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 7).
30 . The method of claim 1 , wherein the modified Cav-1 peptide comprises the amino acid sequence of Ac-aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 8).
31 . The method of claim 1 , wherein the modified Cav-1 peptide comprises the amino acid sequence of OASFTTFTVTOS (SEQ ID NO: 9).
32 . The method of claim 1 , wherein the modified Cav-1 peptide comprises the amino acid sequence of OASFTTFTVTOS-NH2 (SEQ ID NO: 10).
33 . The method of claim 1 , wherein the modified Cav-1 peptide comprises an internalization sequence.
34 . The method of claim 33 , wherein the internalization sequence is located at the C-terminal end of the peptide.
35 . The method of claim 33 , wherein the internalization sequence is located at the N-terminal end of the peptide.
36 . The method of claim 1 , wherein the modified Cav-1 peptide further comprises a cap at the N- and/or C-terminus.
37 . The method of claim 36 , wherein the modified Cav-1 peptide comprises the cap at the N-terminus and C-terminus.
38 . The method of claim 1 , wherein the modified Cav-1 peptide is cyclized.
39 . The method of claim 1 , wherein the modified Cav-1 peptide maintains the biological activity of native Cav-1 (SEQ ID NO: 1)
40 . The method of claim 1 , wherein the modified Cav-1 peptide is a peptide multimer comprising at least two peptides of claim 1 .
41 . The method of claim 40 , wherein a first peptide of the at least two peptides is essentially identical to a second peptide of the at least two peptides.
42 . The method of claim 40 , wherein a first peptide of the at least two peptides is not identical to a second peptide of the at least two peptides.
43 . The method of claim 1 , wherein the modified Cav-1 peptide is administered to the lung.
44 . The method of claim 1 , wherein the modified Cav-1 peptide is formulated for inhalation.
45 . The method of claim 44 , wherein the modified Cav-1 peptide is formulated for pressurized metered dose inhalation.
46 . The method of claim 44 , wherein the modified Cav-1 peptide is formulated for nebulization.
47 . The method of claim 46 , wherein the modified Cav-1 peptide is administered to the subject using a nebulizer.
48 . The method of claim 1 , wherein the modified Cav-1 peptide is formulated as a dry powder.
49 . The method of claim 48 , wherein the dry powder is produced by a milling process.
50 . The method of claim 48 , wherein the dry powder is produced by a spray-drying process.
51 . The method of claim 48 , wherein the dry powder is produced by air jet milling.
52 . The method of claim 48 , wherein the dry powder is produced by ball milling.
53 . The method of claim 48 , wherein the dry powder is produced by wet milling.
54 . The method of claim 48 , wherein the dry powder comprises less than 10% (by weight) of water.
55 . The method of claim 48 , wherein the dry powder comprises less than 1% (by weight) of water.
56 . The method of claim 48 , wherein the dry powder comprising the modified Cav-1 peptide is essentially excipient free.
57 . The method of claim 56 , wherein the dry powder consists of the modified Cav-1 peptide.
58 . The method of claim 1 , wherein the modified Cav-1 peptide comprises a pharmaceutically acceptable carrier.
59 . The method of claim 1 , wherein the method further comprises administering to the subject a therapeutically effective amount of at least one additional therapeutic agent.
60 . The method of claim 59 , wherein the at least one additional therapeutic agent is chloroquine, hydroxychloroquine, remdesivir, favipiravir, lopinavir, or ritonavir.