Agonists of guanylate cyclase and their uses
This invention provides novel guanylate cyclase C (GC-C) agonists and their therapeutic use. The agonists may be used either alone or in combination with one or more additional agents.
1. A peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-94, 119, and 120.
2. The peptide of claim 1 , wherein said peptide is
(SEQ ID NO: 1)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Leu 16 ,
(SEQ ID NO: 32)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Ser 16 ,
(SEQ ID NO: 119)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Thr 16 ,
(SEQ ID NO: 120)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Tyr 16 ,
(SEQ ID NO: 17)
dAsn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -dLeu 16 ,
or
(SEQ ID NO: 56)
pyGlu 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Leu 16 .
3. A pharmaceutical composition comprising: a peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-94, 119, and 120; and a pharmaceutical carrier, excipient, or diluent.
4. The peptide of claim 1 , wherein said peptide increases cGMP production in a cell.
5. The peptide of claim 1 , wherein said peptide is a bicyclic peptide.
6. A composition comprising an inert carrier coated with at least one peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-94, 119, and 120 and an enteric coating, wherein the composition releases the peptide at pH 5.0 or pH 7.0.
7. The composition of claim 6 , wherein said inert carrier is mannitol, lactose, a microcrystalline cellulose, or starch.
8. A method of treating a condition that responds to enhanced cGMP levels in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-94, 119, and 120.
9. The method of claim 8 , wherein said peptide is
(SEQ ID NO: 1)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Leu 16 ,
(SEQ ID NO: 32)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Ser 16 ,
(SEQ ID NO: 119)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Thr 16 ,
(SEQ ID NO: 120)
Asn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Tyr 16 ,
(SEQ ID NO: 17)
dAsn 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -dLeu 16 ,
or
(SEQ ID NO: 56)
pyGlu 1 -Asp 2 -Aad 3 -Cys 4 -Glu 5 -Leu 6 -Cys 7 -Val 8 -Asn 9 -
Val 10 -Ala 11 -Cys 12 -Thr 13 -Gly 14 -Cys 15 -Leu 16 .