IP Library › Granted Patent US 10,626,147

Granted Patent B2

US 10,626,147 · App. 15/312,878 · Granted Apr 21, 2020

Cell penetrating peptides and methods of making and using thereof

Inventors: Dehua Pei (Columbus, OH); Ziqing Qian (Columbus, OH)

C07K7/64 A61K38/05 A61K38/12 A61K38/465 A61K47/64 A61K49/0039 A61K49/0041 A61K49/0043 A61K49/0047 A61K49/0056 C07K7/06 C12Y301/03048 A61K38/00

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Quick Facts

Patent No.: US 10,626,147
App. No.: 15/312,878
Granted: Apr 21, 2020
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed herein are compounds having activity as cell penetrating peptides. In some examples, the compounds can comprise a cell penetrating peptide moiety and a cargo moiety. The cargo moiety can comprise one or more detectable moieties, one or more therapeutic moieties, one or more targeting moieties, or any combination thereof. In some examples, the cell penetrating peptide moiety is cyclic. In some examples, the cell penetrating peptide moiety and cargo moiety together are cyclic. In some examples, the cell penetrating peptide moiety is cyclic and the cargo moiety is appended to the cyclic cell penetrating peptide moiety structure. In some examples, the cargo moiety is cyclic and the cell penetrating peptide moiety is cyclic, and together they form a fused bicyclic system.

Claims (238)

1. A cyclic peptide comprising formula Ia:

or a pharmaceutically acceptable salt thereof,

wherein

AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

AA 7 , AA 8 , and AA 9 are each independently an amino acid; and

m, n and p are independently selected from 0 and 1.

2. The cyclic peptide according to claim 1 , wherein:

m and n are each 0;

p is 1; and

AA 9 is L-glutamine.

3. The cyclic peptide according to claim 1 , wherein:

m is 0;

n and p are each 1;

AA 8 is L-arginine; and

AA 9 is L-glutamine.

4. The cyclic peptide according to claim 1 , wherein:

m is 0;

n and p are each 1;

AA 8 is L-glutamine; and

AA 9 is L-phenylalanine.

5. The cyclic peptide according to claim 1 , wherein the cyclic peptide has a cellular uptake efficiency that is at least about five-fold higher than the cellular uptake efficiency of a peptide having an otherwise identical amino acid sequence in which the amino acids are all L-amino acids.

6. The cyclic peptide according to claim 1 , further comprising a cargo moiety, wherein the cargo moiety comprises a detectable moiety, a therapeutic moiety, a targeting moiety, or a combination thereof.

7. A cyclic peptide comprising formula IIa, IIb, or IIc:

or a pharmaceutically acceptable salt thereof,

wherein

(i) AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

AA 7 , AA 8 , and AA 9 are each independently an amino acid;

m, n and p are independently selected from 0 and 1; and

the cargo moiety comprises a detectable moiety, a therapeutic moiety, a targeting moiety, or a combination thereof;

(ii) AA 1 is L-phenylalanine,

AA 2 is D-phenylalanine;

AA 3 is L-naphthylalanine;

AA 4 is L-arginine;

AA 5 is D-arginine;

AA 6 is L-arginine;

AA 7 , AA 8 , and AA 9 are each independently an amino acid;

m, n and p are independently selected from 0 and 1; and

the cargo moiety comprises a detectable moiety, a therapeutic moiety, a targeting moiety, or a combination thereof.

8. The cyclic peptide according to claim 7 , wherein:

AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m and n are each 0;

p is 1; and

AA 9 is L-glutamine.

9. The cyclic peptide according to claim 7 , wherein:

AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m is 0;

n and p are each 1;

AA 8 is L-arginine; and

AA 9 is L-glutamine.

10. The cyclic peptide according to claim 7 , wherein:

AA 1 is L-phenylalanine,

AA 2 is D-phenylalanine;

AA 3 is L-naphthylalanine;

AA 4 is L-arginine;

AA 5 is D-arginine;

AA 6 is L-arginine;

m is 0;

n and p are each 1;

AA 8 is D-arginine; and

AA 9 is L-glutamine.

11. The cyclic peptide according to claim 7 , wherein the cyclic peptide has a cellular uptake efficiency that is at least about five-fold higher than the cellular uptake efficiency of a peptide having an otherwise identical amino acid sequence in which the amino acids are all L-amino acids.

12. A method for delivering a therapeutic agent to cytoplasm of a cell, comprising administering at least one cyclic peptide comprising formula IIa, IIb, or IIc to a cell:

or a pharmaceutically acceptable salt thereof,

wherein:

(i) AA 1 is phenylalanine;

AA 2 is naphthylalanine;

AA 3 is arginine;

AA 4 is arginine;

AA 5 is arginine;

AA 6 is arginine;

AA 7 , AA 8 , and AA 9 are each independently an amino acid;

m, n and p are independently selected from 0 and 1; and

the cargo comprises a therapeutic agent;

thereby delivering the therapeutic agent to the cytoplasm of the cell;

(ii) AA 1 is phenylalanine,

AA 2 is phenylalanine;

AA 3 is naphthylalanine;

AA 4 is arginine;

AA 5 is arginine;

AA 6 is arginine;

AA 7 , AA 8 , and AA 9 are each independently an amino acid;

m, n and p are independently selected from 0 and 1; and

the cargo comprises a therapeutic agent;

thereby delivering the therapeutic agent to the cytoplasm of the cell.

13. The method of claim 12 , wherein:

AA 1 is L-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is L-arginine;

AA 5 is L-arginine;

AA 6 is L-arginine;

m and n are each 0;

p is 1; and

AA 9 is L-glutamine.

14. The method of claim 12 , wherein:

AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine; and

AA 6 is D-arginine.

15. The method of claim 14 , wherein:

m and n are each 0;

p is 1; and

AA 9 is L-glutamine.

16. The method of claim 14 , wherein:

m is 0;

n and p are each 1;

AA 8 is L-arginine; and

AA 9 is L-glutamine.

17. The method of claim 12 , wherein:

AA 1 is L-phenylalanine,

AA 2 is D-phenylalanine;

AA 3 is L-naphthylalanine;

AA 4 is L-arginine;

AA 5 is D-arginine;

AA 6 is L-arginine;

m is 0;

n and p are each 1;

AA 8 is D-arginine; and

AA 9 is L-glutamine.

18. The method of claim 12 , wherein the therapeutic agent is an inhibitor against Ras, PTP1B, Pin1, Grb2, SH2, or combinations thereof.

19. The method of claim 12 , wherein the cyclic peptide further comprises a detectable moiety, a targeting moiety, or a combination thereof.

20. The cyclic peptide of formula IIa according to claim 7 , wherein:

(i) AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m and n are each 0;

p is 1; and

AA 9 is L-glutamine,

(ii) AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m is 0;

n and p are each 1;

AA 8 is L-arginine; and

AA 9 is L-glutamine,

(iii) AA 1 is L-phenylalanine,

AA 2 is D-phenylalanine;

AA 3 is L-naphthylalanine;

AA 4 is L-arginine;

AA 5 is D-arginine;

AA 6 is L-arginine;

m is 0;

n and p are each 1;

AA 8 is D-arginine; and

AA 9 is L-glutamine.

21. The cyclic peptide of formula IIb according to claim 7 , wherein:

(i) AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m and n are each 0;

p is 1; and

AA 9 is L-glutamine,

(ii) AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m is 0;

n and p are each 1;

AA 8 is L-arginine; and

AA 9 is L-glutamine,

(iii) AA 1 is L-phenylalanine,

AA 2 is D-phenylalanine;

AA 3 is L-naphthylalanine;

AA 4 is L-arginine;

AA 5 is D-arginine;

AA 6 is L-arginine;

m is 0;

n and p are each 1;

AA 8 is D-arginine; and

AA 9 is L-glutamine.

22. The cyclic peptide of formula IIc according to claim 7 , wherein:

(i) AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m and n are each 0;

p is 1; and

AA 9 is L-glutamine,

(ii) AA 1 is D-phenylalanine;

AA 2 is L-naphthylalanine;

AA 3 is L-arginine;

AA 4 is D-arginine;

AA 5 is L-arginine;

AA 6 is D-arginine;

m is 0;

n and p are each 1;

AA 8 is L-arginine; and

AA 9 is L-glutamine,

(iii) AA 1 is L-phenylalanine,

AA 2 is D-phenylalanine;

AA 3 is L-naphthylalanine;

AA 4 is L-arginine;

AA 5 is D-arginine;

AA 6 is L-arginine;

m is 0;

n and p are each 1;

AA 8 is D-arginine; and

AA 9 is L-glutamine.

Assignments (4)

CONFIRMATORY LICENSE Recorded Jan 17, 2024

From: OHIO STATE UNIVERSITY

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 066340/0300 →

CONFIRMATORY LICENSE Recorded Jul 31, 2020

From: THE OHIO STATE UNIVERSITY

To: NIH - DEITR

Reel/Frame 053372/0222 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 22, 2018

From: PEI, DEHUA; QIAN, ZIQING

To: CYCLOPORTERS, INC.

Reel/Frame 044689/0143 →

CHANGE OF NAME Recorded Jan 22, 2018

From: CYCLOPORTERS, INC.

To: ENTRADA THERAPEUTICS, INC.

Reel/Frame 045109/0525 →

Continuity (3)

Provisional Application 62158351 · May 7, 2015

Provisional Application 62001535 · May 21, 2014

Related Publication 20170190743A1 · Jul 6, 2017

Cited By (22)

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