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US 10,744,180 B2Granted
Therapy and kit for the prevention and treatment of cystic fibrosis
AssigneeTrustees of Dartmouth College
InventorsDean R. Madden, Nicholas P. Gill, Carrie Ann Davison, Mark R. Spaller
Life of this patent
Estimating the term…
Abstract
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.
Claims8
A peptidomimetic comprising the sequence NH2-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6 (SEQ ID NO:4), wherein:
- (i) Xaa1 is Met, Phe, Leu, Ala, Trp, diaminobutyric acid, diaminopropionic acid or a residue of Formula I,
- wherein X is —CH2— or —(CH2)n—NH—, m is 1 to 4, n is 1 to 4, and each occurrence of R1 is a tert-butyl group;
- (ii) Xaa2 is Gln, Pro, Phe, S-pipecolic acid or a residue of Formula II,
- wherein R2 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) Xaa3 is Ser, Val, Thr or a residue of Formula III,
- wherein X is —(CH2)n—, n is 1 to 4, and R3 and R4 are independently a hydrogen or methyl group;
- (iv) Xaa4 is Ser, Thr or a residue of Formula IV,
- wherein R5, R6 and R7 are each independently a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group, with the proviso that at least one of R5, R6 or R7 is a hydroxyl group;
- (v) Xaa5 is Lys, Arg, Ile or a residue of Formula V,
- wherein X is —(CH2)n—, n is 1 to 4, and R8 is a substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
- and
- (vi) Xaa6 is Ile, Val, tert-butyl glycine and tert-butyl alanine or a residue of Formula VI,
- wherein X is hydrogen or C1-4 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.
11 more elements
A kit comprising
- (a) peptidomimetic comprising the sequence NH2-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6 (SEQ ID NO:4), wherein:
- (i) Xaa1 is Met, Phe, Leu, Ala, Trp, diaminobutyric acid, diaminopropionic acid or a residue of Formula I,
- wherein X is —CH2— or —(CH2)n—NH—, m is 1 to 4, n is 1 to 4, and each occurrence of R1 is a tert-butyl group;
- (ii) Xaa2 is Gln, Pro, Phe, S-pipecolic acid or a residue of Formula II,
- wherein R2 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) Xaa3 is Ser, Val, Thr or a residue of Formula III,
- wherein X is —(CH2)n—, n is 1 to 4, and R3 and R4 are independently a hydrogen or methyl group;
- (iv) Xaa4 is Ser, Thr or a residue of Formula IV,
- wherein R5, R6 and R7 are each independently a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group, with the proviso that at least one of R5, R6 or R7 is a hydroxyl group;
- (v) Xaa5 is Lys, Arg, Ile or a residue of Formula V,
- wherein X is —(CH2)n—, n is 1 to 4, and R5 is a substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
- and
- (vi) Xaa6 is Ile, Val, tert-butyl glycine and tert-butyl alanine or a residue of Formula VI,
- wherein X is hydrogen or C1-4 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.
14 more elements
A method for treating cystic fibrosis comprising administering to a subject in need of treatment an effective amount of a peptidomimetic comprising the sequence NH2-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6 (SEQ ID NO:4), wherein:
- (i) Xaa1 is Met, Phe, Leu, Ala, Trp, diaminobutyric acid, diaminopropionic acid or a residue of Formula I,
- wherein X is —CH2— or —(CH2)n—NH—, m is 1 to 4, n is 1 to 4, and each occurrence of R1 is a tert-butyl group;
- (ii) Xaa2 is Gln, Pro, Phe, S-pipecolic acid or a residue of Formula II,
- wherein R2 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) Xaa3 is Ser, Val, Thr or a residue of Formula III,
- wherein X is —(CH2)n—, n is 1 to 4, and R3 and R4 are independently a hydrogen or methyl group;
- (iv) Xaa4 is Ser, Thr or a residue of Formula IV,
- wherein R5, R6 and R7 are each independently a hydrogen, hydroxyl, methyl, amino, cyano, halo, nitro, mercapto, or phosphate group, with the proviso that at least one of R5, R6 or R7 is a hydroxyl group;
- (v) Xaa5 is Lys, Arg, Ile or a residue of Formula V,
- wherein X is —(CH2)n—, n is 1 to 4, and R8 is a substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
- and
- (vi) Xaa6 is Ile, Val, tert-butyl glycine and tert-butyl alanine or a residue of Formula VI,
- wherein X is hydrogen or C1-4 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.
11 more elements
Dependencies are inferred from the claim text.