IP Library › Granted Patent US 12,281,181
Granted Patent B2
US 12,281,181 · App. 18/333,516 · Granted Apr 22, 2025

Bicyclic peptidyl inhibitors

Inventor: Dehua Pei (Columbus, OH)
Assignee: Ohio State Innovation Foundation
C07K7/64A61P35/00
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Quick Facts
Patent No.
US 12,281,181
App. No.
18/333,516
Granted
Apr 22, 2025
Kind
B2
Abstract

The present disclosure provides a large combinatorial library of cell-permeable bicyclic peptides. The bicyclic peptides described herein include the first ring consisted of randomized peptide sequences for potential binding to a target of interest while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the IκB kinase α/β (IKKα/β)-binding domain of NF-κB essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides which inhibited the NEMO-IKKβ interaction, thereby selectively inhibiting canonical NF-κB signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells.

Claims (23)

1. A bicyclic polypeptide according to Formula 1A or 1B:

wherein:

CPP is a cell-penetrating peptide sequence selected from any one of SEQ ID NO.: 11-48 or 66-99;

Xm is a peptide sequence that binds NF-κB essential modulator (NEMO) protein and is a 4-7 amino acid sequence comprising a sequence selected from any one of GWIY (SEQ ID NO: 1); GWIYA (SEQ ID NO:2); GWIYa (SEQ ID NO:50); AGWIY (SEQ ID NO:3); aGWIY (SEQ ID NO:51); AWIYA (SEQ ID NO:4); GAIYA (SEQ ID NO:5); GWAYA (SEQ ID NO: 6); GWIAA (SEQ ID NO:7); GWIYA (SEQ ID NO:8); GAIAA (SEQ ID NO:9); and GAAAA (SEQ ID NO:10), and the inverse of the aforementioned Xm sequences (SEQ ID Nos: 52-63);

L is a linker moiety; and

each of R 1 , R 2 , and R 3 are independently, a bonding moiety,

wherein the bonding moiety is formed when Xm, CPP, or a combination thereof, covalently bind to L to form the bicyclic polypeptide.

2. A bicyclic polypeptide according to Formula 1C or 1D:

wherein:

CPP is a cell-penetrating peptide sequence selected from any one of SEQ ID NO.: 11-48 or 66-99;

Xm is a peptide sequence that binds to a NF-κB essential modulator (NEMO) protein and is a 4-7 amino acid sequence comprising a sequence selected from any one of GWIY (SEQ ID NO:1); GWIYA (SEQ ID NO:2); GWIYa (SEQ ID NO:50); AGWIY (SEQ ID NO:3); aGWIY (SEQ ID NO:51); AWIYA (SEQ ID NO:4); GAIYA (SEQ ID NO:5); GWAYA (SEQ ID NO:6); GWIAA (SEQ ID NO:7); GWIYA (SEQ ID NO:8); GAIAA (SEQ ID NO:9); and GAAAA (SEQ ID NO: 10), and the inverse of the aforementioned Xm sequences (SEQ ID Nos: 52-63);

AA L at each instance is an amino acid;

p is selected from a number from 0 to 3;

L is a linker moiety; and

each of R 1 , R 2 , and R 3 are independently, a bonding moiety,

wherein the bonding moiety is formed when Xm, CPP, or a combination thereof, covalently bind to L to form the bicyclic polypeptide.

3. The bicyclic polypeptide of claim 1 , wherein both the CPP sequence and the Xm sequence participate in binding to NEMO.

4. The bicyclic polypeptide of claim 1 , wherein the polypeptide binds to the IKKα/β-binding domain on NEMO.

5. The bicyclic polypeptide of claim 1 , wherein the polypeptide inhibits NEMO-IKKα/β interaction by at least about 10%.

6. The bicyclic polypeptide of claim 1 , wherein the polypeptide has an IC50 of about 10 UM or less when measured for the NEMO-IKKα/β interaction.

7. The bicyclic polypeptide of claim 1 , wherein the polypeptide has an IC50 of about 1.0 uM or less when measured for the NEMO-IKKα/β interaction.

8. The bicyclic polypeptide of claim 1 , wherein each of R 1 , R 2 , and R 3 are independently selected from an amide, an ester, and triazole, and combinations thereof.

9. A pharmaceutical composition comprising the bicyclic polypeptide of claim 1 and one or more pharmaceutically acceptable excipients.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 22, 2023
From: PEI, DEHUA
To: OHIO STATE INNOVATION FOUNDATION
Reel/Frame 064994/0682 →
Continuity (4)
Continuation 17750966 · May 23, 2022
Division 16753681
Provisional Application 62568221 · Oct 4, 2017
Related Publication 20230322859A1 · Oct 12, 2023
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