Therapy and kit for the prevention and treatment of cystic fibrosis
Compositions, kits and methods for preventing or treating cystic fibrosis are provided, which include the use of a peptidomimetic that inhibits the interaction between CAL and mutant CFTR proteins.
1. A peptidomimetic comprising the sequence NH 2 -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 (SEQ ID NO:4), wherein:
(i) Xaa 1 is Met, Phe, Leu, Ala, Trp, diaminobutyric acid, diaminopropionic acid or a residue of Formula I,
wherein X is —CH 2 — or —(CH 2 ) n —NH—, m is 1 to 4, n is 1 to 4, and each occurrence of R 1 is a tert-butyl group;
(ii) Xaa 2 is Gln, Pro, Phe, S-pipecolic acid or a residue of Formula II,
wherein R 2 is substituted at least one time anywhere on the ring and is a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group;
(iii) Xaa 3 is Ser, Val, Thr or a residue of Formula III,
wherein X is —(CH 2 ) n —, n is 1 to 4, and R 3 and R 4 are independently a hydrogen or methyl group;
(iv) Xaa 4 is Ser, Thr or a residue of Formula IV,
wherein R 5 , R 6 and R 7 are each independently a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group, with the proviso that at least one of R 5 , R 6 or R 7 is a hydroxyl group;
(v) Xaa 5 is Lys, Arg, Ile or a residue of Formula V,
wherein X is —(CH 2 ) n —, n is 1 to 4, and R 8 is a substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and
(vi) Xaa 6 is Ile, Val, tert-butyl glycine and tert-butyl alanine or a residue of Formula VI,
wherein X is hydrogen or C 1-4 alkyl;
with the proviso that the peptidomimetic includes at least one of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI.
2. The peptidomimetic of claim 1 , further comprising a label, one or more post-translational modifications, and/or a cell-penetrating sequence.
3. A pharmaceutical composition comprising the peptidomimetic of claim 1 in admixture with a pharmaceutically acceptable carrier.
4. The pharmaceutical composition of claim 3 , further comprising a CFTR corrector, CFTR potentiator, mucolytic, anti-inflammatory agent or a combination thereof.
5. A kit comprising
(a) peptidomimetic comprising the sequence NH 2 -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 (SEQ ID NO:4), wherein:
(i) Xaa 1 is Met, Phe, Leu, Ala, Trp, diaminobutyric acid, diaminopropionic acid or a residue of Formula I,
wherein X is —CH 2 — or —(CH 2 ) n —NH—, m is 1 to 4, n is 1 to 4, and each occurrence of R 1 is a tert-butyl group;
(ii) Xaa 2 is Gln, Pro, Phe, S-pipecolic acid or a residue of Formula II,
wherein R 2 is substituted at least one time anywhere on the ring and is a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group;
(iii) Xaa 3 is Ser, Val, Thr or a residue of Formula III,
wherein X is —(CH 2 ) n —, n is 1 to 4, and R 3 and R 4 are independently a hydrogen or methyl group;
(iv) Xaa 4 is Ser, Thr or a residue of Formula IV,
wherein R 5 , R 6 and R 7 are each independently a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group, with the proviso that at least one of R 5 , R 6 or R 7 is a hydroxyl group;
(v) Xaa 5 is Lys, Arg, Ile or a residue of Formula V,
wherein X is —(CH 2 ) n —, n is 1 to 4, and R 5 is a substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and
(vi) Xaa 6 is Ile, Val, tert-butyl glycine and tert-butyl alanine or a residue of Formula VI,
wherein X is hydrogen or C 1-4 alkyl;
with the proviso that the peptidomimetic includes at least one of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI; and
(b) a CFTR corrector, CFTR potentiator, mucolytic, anti-inflammatory agent or a combination thereof.
6. The kit of claim 5 , wherein the peptidomimetic further comprises a label, one or more post-translational modifications, and/or a cell-penetrating sequence.
7. A method for treating cystic fibrosis comprising administering to a subject in need of treatment an effective amount of a peptidomimetic comprising the sequence NH 2 -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 (SEQ ID NO:4), wherein:
(i) Xaa 1 is Met, Phe, Leu, Ala, Trp, diaminobutyric acid, diaminopropionic acid or a residue of Formula I,
wherein X is —CH 2 — or —(CH 2 ) n —NH—, m is 1 to 4, n is 1 to 4, and each occurrence of R 1 is a tert-butyl group;
(ii) Xaa 2 is Gln, Pro, Phe, S-pipecolic acid or a residue of Formula II,
wherein R 2 is substituted at least one time anywhere on the ring and is a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group;
(iii) Xaa 3 is Ser, Val, Thr or a residue of Formula III,
wherein X is —(CH 2 ) n —, n is 1 to 4, and R 3 and R 4 are independently a hydrogen or methyl group;
(iv) Xaa 4 is Ser, Thr or a residue of Formula IV,
wherein R 5 , R 6 and R 7 are each independently a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group, with the proviso that at least one of R 5 , R 6 or R 7 is a hydroxyl group;
(v) Xaa 5 is Lys, Arg, Ile or a residue of Formula V,
wherein X is —(CH 2 ) n —, n is 1 to 4, and R 8 is a substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and
(vi) Xaa 6 is Ile, Val, tert-butyl glycine and tert-butyl alanine or a residue of Formula VI,
wherein X is hydrogen or C 1-4 alkyl;
with the proviso that the peptidomimetic includes at least one of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, thereby treating the subject's cystic fibrosis.
8. The method of claim 7 , further comprising administering a CFTR corrector, CFTR potentiator, mucolytic, anti-inflammatory agent or a combination thereof.