Granted Patent
B2
US 12,496,350 · App. 18/468,151 · Granted Dec 16, 2025
Cyclic peptidyl inhibitors of CAL-PDZ binding domain
Assignee:
Ohio State Innovation Foundation
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Abstract
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.
Claims (32)
1 . A peptide having a structure according to Formula I or II:
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, 1 or 2;
n is a number in the range of from 2 to 5;
p is a number in the range of from 0 to 10;
each of AA S1 and AA S2 is independently an amino acid that forms a disulfide bond (ss) each selected from:
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 and comprises two or three hydrophobic amino acids and one or two arginines.
2 . The peptide of claim 1 , wherein n is 2 or 3.
3 . The peptide of claim 1 , wherein three of AA 1 , AA 2 , AA 3 , AA 4 , and A 5 are arginine.
4 . The peptide of claim 1 , wherein one of AA 1 , AA 2 , AA 3 , AA 4 , and A 5 is naphthylalanine.
5 . The peptide of claim 1 , wherein one of AA 1 , AA 2 , AA 3 , AA 4 , and A 5 is 3-(3-benzothienyl)-alanine.
6 . The peptide of claim 1 , wherein one of AA 1 , AA 2 , AA 3 , AA 4 , and A 5 is naphthylalanine and one of AA 1 , AA 2 , AA 3 , AA 4 , and A 5 is 3-(3-benzothienyl)-alanine.
7 . The peptide of claim 1 , wherein the two or three hydrophobic amino acids comprised in
-AA 6 -AA 7 -AA 8 -(AA 9 ) n is selected from valine, leucine, isoleucine, phenylalanine, tryptophan, proline, naphthylalanine, and phenylalanine.
8 . The peptide of claim 1 , wherein -AA 6 -AA 7 -AA 8 -(AA 9 ) n are each, independently, tryptophan, glutamine, valine, phenylalanine, lysine, arginine, leucine, or threonine.
9 . The peptide of claim 1 , wherein n is 3 and -AA 6 -AA 7 -AA 8 -(AA 9 ) n are each, independently, tryptophan, glutamine, valine, phenylalanine, lysine, arginine, leucine, or threonine.
10 . The peptide of claim 9 , wherein AA 6 is tryptophan.
11 . The peptide of claim 9 , wherein AA 7 is glutamine.
12 . The peptide of claim 9 , wherein AA 8 is selected from valine, phenylalanine, lysine, arginine, or leucine.
13 . The peptide of claim 9 , wherein at least one AA 9 is threonine.
14 . The peptide of claim 13 , wherein at least one AA 9 is arginine, lysine, leucine, valine, or isoleucine.
15 . The peptide of claim 1 , wherein:
in Formula I:
when p is 1 to 10, the N-terminus of AA 10 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.
16 . The peptide of claim 1 , wherein at least one of AA S1 and AA S2 is:
17 . The peptide of claim 1 , wherein at least one of AA S1 and AA S2 is:
18 . A pharmaceutical composition comprising the peptide of claim 1 .
19 . A method of treating cystic fibrosis in a patient in need thereof, comprising administering a peptide of claim 1 to the patient.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 17, 2025
From: PEI, DEHUA; DOUGHERTY, PATRICK G.
To: OHIO STATE INNOVATION FOUNDATION
Reel/Frame 072278/0574 →
Continuity (3)
Continuation
16965713
Provisional Application
62623209
· Jan 29, 2018
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