SP-B and SP-C peptides, synthetic lung surfactants, and use thereof
The present invention relates to synthetic lung surfactant compositions that include a novel surface active peptide and a phospholipid, including phospholipase-resistant phospho-glycerol derivatives, phospholipase-resistant phospho-choline derivatives, naturally occurring phospholipids, or a combination thereof. Uses of the surfactant compositions of the present invention to treat endogenous surfactant dysfunctional or deficient lung tissue and to deliver therapeutic agents are also disclosed.
1. An isolated peptide comprising the amino acid sequence according to one of:
(i)
(SEQ ID NO: 1)
X WL X RALIKRIQAMI-Z-RMLPQLV X RLVLR X S,
where Z is a loop or turn sequence consisting of four to ten amino acid residues that include peptides DATK (SEQ ID NO: 501), DHGS (SEQ ID NO: 502), HSGD (SEQ ID NO: 503), or EAGD (SEQ ID NO: 504), and each X independently represents an uncharged amino acid residue, and
(ii)
(SEQ ID NO: 414)
X WL X RALIKRIQA X I- Z -R X LPQLV X RLVLR X S,
where Z is a loop or turn sequence consisting of four to ten amino acid residues that include peptides DATK (SEQ ID NO: 501), DHGS (SEQ ID NO: 502), HSGD (SEQ ID NO: 503), or EAGD (SEQ ID NO: 504), each X at positions 1, 4, 24, and 30 independently represents an uncharged amino acid residue and each X at positions 14 and 18 independently represents leucine, isoleucine, or norleucine.
2. The isolated peptide according to claim 1 wherein the peptide is selected from the group of SEQ ID NOS: 4-15, 18-29, 417-428, 431-442, 445-456, 459-470, 473-484, and 487-498.
3. The isolated peptide according to claim 1 wherein the peptide includes a cysteine residue and the isolated peptide is in the form of a dimer linked via disulfide bond.
4. The isolated peptide according to claim 1 wherein the peptide further comprises a fatty acid chain covalently-linked to an amino acid residue.
5. A surfactant composition comprising a peptide according to claim 1 and a phospholipid.
6. The surfactant composition according to claim 5 , wherein the phospholipid is phospholipase-resistant.
7. The surfactant composition according to claim 5 , wherein the phospholipid is a naturally occurring phospholipid.
8. The surfactant composition according to claim 5 further comprising a non-phospho surfactant.
9. The surfactant composition according to claim 5 further comprising a therapeutic agent.
10. The surfactant composition according to claim 5 wherein the composition comprises:
Weight percent
component
about 85 to about 96
DEPN-8 or diether C16:0 saturated PC analog
about 2.5 to about
C16:0, C18:1 diether phosphono- or phospho-PG
10
up to about 7
Palmitic acid
about 1 to about 4
at least one of SMB_DATK (SEQ ID NO: 18,
(relative to total
reduced or oxidized), MB_DATK (SEQ ID
lipid content)
NO: 4, reduced or oxidized), and
MB_DATK_Ala (SEQ ID NO: 5)
about 1 to about 4
at least one of Mini-SPCff_dog (SEQ ID NO: 31),
(relative to total
Mini-SPCff_dog_leu (SEQ ID NO: 32), Mini-
lipid content)
SPCff_2_leu (SEQ ID NO: 34), Super Mini-SP-C
(SEQ ID NO: 35)), SP-Css ion-lock (SEQ ID NO:
45), SP-C ion-lock (SEQ ID NO: 406), SP-C ion-
lock2ss (SEQ ID NO: 197), SP-C ion-lock-dog
(SEQ ID NO: 61), SP-C ion-lock2ff (SEQ ID NO:
69), and SP-C33ss_ion2 (SEQ ID NO: 326).
11. The surfactant composition according to claim 5 wherein the composition comprises:
Weight percent
component
about 70 to about 95
dipalmitoyl phosphatidylcholine (DPPC)
about 5 to about 25
palmitoyl-oleoyl-phosphatidylglycerol (POPG)
up to about 25
palmitoyl-oleoyl-phosphatidylcholine (POPC)
about 1 to about 7.5
SMB_DATK (SEQ ID NO: 18, reduced or oxidized),
(relative to total
MB_DATK (SEQ ID NO: 4, reduced or oxidized),
lipid content)
MB_DATK_ Ala (SEQ ID NO: 5),
or combinations thereof.
12. The surfactant composition according to claim 5 wherein the composition comprises:
Weight percent
component
about 70 to about 95
dipalmitoyl phosphatidylcholine (DPPC)
about 5 to about 25
palmitoyl-oleoyl-phosphatidylglycerol (POPG)
up to about 25
palmitoyl-oleoyl-phosphatidylcholine (POPC)
up to about 7
Palmitic acid
about 1 to about 4
at least one of SMB_DATK (SEQ ID NO: 18,
(relative to total
reduced or oxidized), MB_DATK (SEQ ID NO: 4,
lipid content)
reduced or oxidized), and MB_DATK_Ala
about 1 to about 4
(SEQ ID NO: 5) at least one of Mini-SPCff_dog
(relative to total
(SEQ ID NO: 31), Mini-SPCff_dog_leu
lipid content)
(SEQ ID NO: 32), Mini-SPCff_2_leu (SEQ
ID NO: 34), Super Mini-SP-C (SEQ ID NO: 35) ),
SP-Css ion-lock (SEQ ID NO: 45), SP-C ion-lock
(SEQ ID NO: 406), SP-C ion-1ock2ss
(SEQ ID NO: 197), SP-C ion-lock-dog
(SEQ ID NO: 61), SP-C
ion-1ock2ff (SEQ ID NO: 69), and
SP-C33ss_ion2 (SEQ ID NO: 326).
13. The isolated peptide of claim 1 , wherein each X at positions 1, 4, 24, and 30 of SEQ ID NO: 1 and SEQ ID NO: 414 independently represents Val, Ile, Leu, Met, Phe, His, Tyr, Gly, Ala, Cys, Pro, Asn, Gln, Ser, or Thr.
14. A method of treating endogenous surfactant deficiency and/or dysfunctional lung tissue comprising:
providing a surfactant composition according to claim 5 ; and
administering the surfactant composition to a patient having lung tissue characterized by endogenous surfactant deficiency and/or dysfunction, wherein said administering coats alveolar surfaces of the affected lung tissue with the surfactant composition, thereby treating the surfactant deficient and/or dysfunctional lung tissue.
15. A method of delivering a therapeutic agent comprising:
introducing a therapeutic agent into a surfactant composition according to claim 5 ; and
administering the composition to a subject to deliver the therapeutic agent to a target tissue.