Synthetic lung surfactant and use thereof
The present invention relates to synthetic lung surfactant compositions that contain one or more of phospholipase-resistant phospho-glycerol derivatives, phospholipase-resistant phospho-choline derivatives, and surface active proteins or peptides, more preferably a combination of at least two or all three of these materials. Novel phospholipase-resistant phospho-glycerol derivatives, phospholipase-resistant phospho-choline derivatives, and surface active peptides are also disclosed herein. Uses of the surfactant compositions of the present invention to treat endogenous surfactant dysfunctional or deficient lung tissue, to prepare synthetic peptides for use in the surfactant compositions, and to deliver therapeutic agents are also disclosed.
1. A surface active peptide selected from the group consisting of
SEQ ID NO: 5
CWFCRFFFKRFFFFFPKGGRFFPFFFCRFFFRCS,
SEQ ID NO: 6
CWFCRAFIKRFQAMIPKGGRMLPQLVCRLVLRCS,
SEQ ID NO: 7
CWLCRALIKRIQAMIPKGGRMFPQFFCRFFFRCS,
SEQ ID NO: 8
CWFCRAFIKRFQAMIPKGGRMFPQFFCRFFFRCS,
SEQ ID NO: 9
CWFCRAFIKRFQAMIPKGERMLPQLVCRLVLRCS,
SEQ ID NO: 10
CWLCRALIKRIQAMIPKGERMFPQFFCRFFFRCS,
SEQ ID NO: 11
CWFCRAFIKRFQAMIPKGERMFPQFFCRFFFRCS,
SEQ ID NO: 12
CWLCRALIKRIQAMIPXGGRMLPQLVCRLVLRCS,
where X is Cysteine,
SEQ ID NO: 13
FPIPLPYCWLCRALIKRIQAMIPKGGRMLPQLVCRLVLRCS,
SEQ ID NO: 14
FPCPLPYCWLCRALIKRIQAMIPKGGRMLPQLVCRLVLRCS,
SEQ ID NO: 15
CPIPLPYCWLCRALIKRIQAMIPKGGRMLPQLVCRLVLRCS,
SEQ ID NO: 16
CWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVAGGICQALAERYS
VILLDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 17
CWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVAGGICQFLAERYSV
ILLDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 18
FPIPLPYCWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVVGGICQYL
AERYSVILLDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 19
CPIPLPYCWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVVGGICQY
LAERYSVILLDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 20
FPCPLPYCWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVVGGICQY
LAERYSVILLDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 21
FGIPFFPVHLKRLLVVVVVVVLVVVVIVGALLMGL,
SEQ ID NO: 22
FGIPFFPVHLKRLLVPVVVVVLVVVVIVGALLMGL,
SEQ ID NO: 23
FGIPFFPVHLKRLLVVVVVPVLVVVVIVGALLMGL,
SEQ ID NO: 24
FGIPFFPVHLKRLLVVVVVVVLVPVVIVGALLMGL,
SEQ ID NO: 25
FGIPFFPVHLKRLLVVVVVVVLVVVVIPGALLMGL,
and combinations thereof.
2. The surface active peptide according to claim 1 wherein the surface active peptide is selected from the group of
SEQ ID NO: 5
CWFCRFFFKRFFFFFPKGGRFFPFFFCRFFFRCS,
SEQ ID NO: 6
CWFCRAFIKRFQAMIPKGGRMLPQLVCRLVLRCS,
SEQ ID NO: 7
CWLCRALIKRIQAMIPKGGRMFPQFFCRFFFRCS,
SEQ ID NO: 8
CWFCRAFIKRFQAMIPKGGRMFPQFFCRFFFRCS,
SEQ ID NO: 9
CWFCRAFIKRFQAMIPKGERMLPQLVCRLVLRCS,
SEQ ID NO: 10
CWLCRALIKRIQAMIPKGERMFPQFFCRFFFRCS,
SEQ ID NO: 11
CWFCRAFIKRFQAMIPKGERMFPQFFCRFFFRCS,
SEQ ID NO: 12
CWLCRALIKRIQAMIPXGGRMLPQLVCRLVLRCS,
where X is Cysteine,
SEQ ID NO: 13
FPIPLPYCWLCRALIKRIQAMIPKGGRMLPQLVCRLVLRCS,
SEQ ID NO: 14
FPCPLPYCWLCRALIKRIQAMIPKGGRMLPQLVCRLVLRCS,
SEQ ID NO: 15
CPIPLPYCWLCRALIKRIQAMIPKGGRMLPQLVCRLVLRCS,
and combinations thereof.
3. The surface active peptide according to claim 2 wherein the surface active peptide is a dimer comprising (i) two monomer units according to SEQ ID NO: 12, or (ii) two monomer units according to SEQ ID NO: 14 or SEQ ID NO: 15 or both.
4. The surface active peptide according to claim 1 wherein the surface active peptide is selected from the group of
SEQ ID NO: 16
CWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVAGGICQALAERYSVIL
LDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 17
CWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVAGGICQFLAERYSVIL
LDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 18
FPIPLPYCWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVVGGICQYLA
ERYSVILLDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 19
CPIPLPYCWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVVGGICQYLA
ERYSVILLDTLLGRMLPQLVCRLVLRCS,
SEQ ID NO: 20
FPCPLPYCWLCRALIKRIQAMIPKGALAVAVAQVCRVVPLVVGGICQYLA
ERYSVILLDTLLGRMLPQLVCRLVLRCS,
and combinations thereof.
5. The surface active peptide according to claim 4 wherein the surface active peptide is a dimer comprising two monomer units according to SEQ ID NO: 19 or SEQ ID NO: 20 or both.
6. The surface active peptide according to claim 1 wherein the surface active peptide is selected from the group of
FGIPFFPVHLKRLLVVVVVVVLVVVVIVGALLMGL,
SEQ ID NO: 21
FGIPFFPVHLKRLLVPVVVVVLVVVVIVGALLMGL,
SEQ ID NO: 22
FGIPFFPVHLKRLLVVVVVPVLVVVVIVGALLMGL,
SEQ ID NO: 23
FGIPFFPVHLKRLLVVVVVVVLVPVVIVGALLMGL,
SEQ ID NO: 24
FGIPFFPVHLKRLLVVVVVVVLVVVVIPGALLMGL,
SEQ ID NO: 25
and combinations thereof.
7. A surfactant composition comprising a phospholipid and a surface active peptide according to claim 1 .
8. The surfactant composition according to claim 7 , wherein the phospholipid is phospholipase-resistant.
9. The surfactant composition according to claim 8 , wherein the phospholipase-resistant phospholipid comprises a phospholipase-resistant phosphoglycerol derivative, a phospho lipase-resistant phosphocho line derivative, and combinations thereof.
10. The surfactant composition according to claim 7 , wherein the phospholipid is not phospholipase-resistant.
11. A method of treating endogenous surfactant dysfunctional lung tissue comprising:
providing a surfactant composition according to claim 7 ; and
administering the surfactant composition to a patient having lung tissue characterized by endogenous surfactant dysfunction, wherein said administering is carried out under conditions effective to coat alveolar surfaces of the affected lung tissue with the surfactant composition, thereby treating the surfactant dysfunctional lung tissue.
12. The method according to claim 11 , wherein said administering is effective to prevent the onset or reduce the severity of respiratory deficit of neonatal respiratory distress syndrome, clinical acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS).
13. The method according to claim 11 , wherein said administering is carried out by aspiration, airway instillation, aerosolization, or nebulization.
14. A method of delivering a therapeutic agent to lung tissue of a patient comprising:
introducing a therapeutic agent into a surfactant composition according to claim 7 under conditions effective to encapsulate the therapeutic agent in liposomal vesicles; and
administering the surfactant composition comprising the therapeutic agent encapsulated in liposomal vesicles to a patient under conditions effective to deliver the therapeutic agent to lung tissue of the patient.
15. The surfactant composition according to claim 7 further comprising a peptide according to SEQ ID NO: 4.
16. The surfactant composition according to claim 9 wherein the phospholipase-resistant phospho-glycerol derivative has a structure according to formulae (Ia) or (Ib)
wherein,
X is O or (CH 2 ) n where n is an integer from 0 to 5;
Y 1 and Y 2 are independently O, S, or SO 2 ; and
R 1 and R 2 are independently C8-C24 hydrocarbons.
17. The surfactant composition according to claim 16 , wherein the phospholipase-resistant phospho-glycerol derivative is selected from the group consisting of 2,3-bis(hexadecyloxy)propyl 2,3-dihydroxypropyl hydrogen phosphate; 2-((Z)-hexadec-9-enyloxy)-3-(hexadecyloxy)propyl 2,3-dihydroxypropyl hydrogen phosphate; 2,3-bis(hexadecyloxy)propyl hydrogen 3,4-dihydroxybutylphosphonate; 2-(hexadecyloxy)-3-(hexadecylthio)propyl 2,3-dihydroxypropyl hydrogen phosphate; 2-(hexadecyloxy)-3-(hexadecylsulfonyl)propyl 2,3-dihydroxypropyl hydrogen phosphate; 2-((E)-hexadec-9-enyloxy)-3-(hexadecylthio)propyl 2,3-dihydroxypropyl hydrogen phosphate; 2-((E)-hexadec-9-enyloxy)-3-(hexadecylsulfonyl)propyl 2,3-dihydroxypropyl hydrogen phosphate; 2-(hexadecyloxy)-3-(hexadecylthio)propyl hydrogen 3,4-dihydroxybutylphosphonate; 2-(hexadecyloxy)-3-(hexadecylsulfonyl)propyl hydrogen 3,4-dihydroxybutylphosphonate; 2-((E)-hexadec-9-enyloxy)-3-(hexadecylthio)propyl hydrogen 3,4-dihydroxybutylphosphonate; 2-((E)hexadec-9-enyloxy)-3-(hexadecylsulfonyl)propyl hydrogen 3,4-dihydroxybutylphosphonate; and combinations thereof.
18. The surfactant composition according to claim 9 , wherein the phospholipase-resistant phospho-choline derivative has a structure according to formula (II)
wherein,
X is O or (CH 2 ) n where n is an integer from 0 to 5;
Y 3 and Y 4 are independently O, S, or SO 2 ; and
R 3 and R 4 are independently C8-C24 hydrocarbons.
19. The surfactant composition according to claim 18 , wherein the phospholipase-resistant phospho-choline derivative is selected from the group consisting of [(+)-trimethyl(3-phosphonopropyl)ammonium, mono(2,3-bis(hexadecyloxy)propyl ester]; [(+)-trimethyl(3-phosphonopropyl)ammonium, mono (2-hexadec-9- enyloxy-3-hexadecyloxypropyl) ester] (“DEPN-8”); [(+)-trimethyl(3-phosphonopropyl)ammonium, mono(2-hexadecylo xy-3-hexadecylsulfanylpropyl) ester]; [(+)-trimethyl(3-phosphonopropyl)ammonium, mono(2-hexadecyloxy-3-hexadecylsulfonylpropyl) ester]; and combinations thereof.
20. The surfactant composition according to claim 9 , wherein the phospholipase-resistant phospho-glycerol derivative and the phospholipase-resistant phospho-choline derivative are present in a ratio of between about 1:1 up to about 1:100.
21. The surfactant composition according to claim 7 , wherein the phospholipid is a glycerophospholipid.