Cyclic peptidyl inhibitors of CAL-PDZ binding domain
Described herein, in various embodiments, are peptides comprising: (i) a cyclic cell-penetrating peptide sequence (cCPP) and (ii) a CAL-PDZ binding sequence, which is conjugated, directly or indirectly, to an N-terminus of an amino acid in the cCPP, to a C-terminus of an amino acid on the cCPP, or on a side chain of an amino acid in the cCPP. In other embodiments, the peptides further comprise a physiologically cleavable group, wherein after entering the cell, the physiologically cleavable group is reduced, thereby providing a linear peptide. Without being bound by theory, the inventors discovered that the amino acid sequence in the cCPP, which facilities cytosolic delivery of the CAL-PDZ binding sequence also, surprisingly and unexpectedly, synergistically improves binding of CAL-PDZ binding sequence to the CAL-PDZ binding domain. Additionally, the cCPP sequence may also improve selectivity of the CAL-PDZ binding sequence for the CAL-PDZ domain relative to other PDZ binding domains.
1. A peptide having a structure according to Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
AA 1 , AA 2 , AA 3 , AA 4 , AA 5 , AA 6 , AA 7 , AA 8 , AA 9 , and AA 10 are independently selected from an amino acid, which is optionally substituted with one or more substituents;
m is 0 or 1;
n is a number in the range of from 0 to 10;
p is a number in the range of from 0 to 10;
each of AA S1 and AA S2 is independently an amino acid which forms a disulfide bond (ss);
two or three of AA 1 , AA 2 , AA 3 , AA 4 and A 5 are arginine; and
two or three of AA 1 , AA 2 , AA 3 , AA 4 and A 5 are each independently phenylalanine, naphthylalanine, tryptophan, 3-(3-benzothienyl)-alanine or proline;
-AA 6 -AA 7 -AA 8 -(AA 9 ) n is a peptide sequence which binds to the CAL-PDZ domain is selected from SEQ ID NO: 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, and 119.
2. The peptide of claim 1 , comprising from 1 to 4 D-arginines.
3. The peptide of claim 1 , wherein:
in Formula I:
when p is 1 to 10, the N-terminus of AA is C(O)-alkyl, —C(O)-carbocyclyl, —C(O)-aryl, —C(O)-heteroaryl, or —N(═S)N—R a R b , wherein R a and R b are independently selected from hydrogen, alkyl, carbocyclyl, aryl, and heteroaryl.
4. The peptide of claim 1 , wherein each of AA S1 and AA S2 is:
5. A pharmaceutical composition comprising the peptide of claim 1 .
6. A method of treating cystic fibrosis in a patient in need thereof, comprising administering a peptide of claim 1 to the patient.
7. A peptide having the following structure:
8. A peptide having the following structure: