IP Library › Granted Patent US 10,253,071
Granted Patent B2
US 10,253,071 · App. 14/895,606 · Granted Apr 9, 2019

Selectin inhibitors, composition, and uses related thereto

Inventors: Richard D. Cummings (Atlanta, GA); Elliot L. Chaikof (Newton, MA); Venkata R. Krishnamurthy (Ashland, MA); Mohammed Sardar (Malden, MA)
Assignees: Beth Israel Deaconess Medical Center, Inc.; Emory University
C07K9/00C07K7/08C07K14/70564A61K38/00
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Quick Facts
Patent No.
US 10,253,071
App. No.
14/895,606
Granted
Apr 9, 2019
Kind
B2
Abstract

This disclosure relates to selectin inhibitors, compositions, and methods related thereto. In certain embodiments, the disclosure relates to glycopeptides that contain one more modified amino acids conjugated to a saccharide or polysaccharide. In certain embodiments, the disclosure relates to uses of the glycopeptides as anti-inflammatory, anti-thrombotic, or anti-metastatic agents.

Claims (103)

1. A glycopeptide comprising Y 1 X 1 Y 2 X 2 X 3 Y 3 X 4 X 5 X 6 Z 1 X 7 W 1 (SEQ ID NO: 1) or salts thereof, wherein

W 1 is threonine or serine substituted with a saccharide or polysaccharide,

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each individually and independently any amino acid,

Y 1 , Y 2 , and Y 3 are each individually and independently tyrosine, phenylalanine, or phenylglycine, and wherein Y 1 , Y 2 , and Y 3 are each independently unsubstituted or substituted with —SO 3 H, —CH 2 SO 3 H, —CF 2 SO 3 H, —CO 2 H, —CONH 2 , —NHSO 2 CH 3 , —SO 2 NH 2 , or —CH 2 PO 3 H,

wherein at least one of Y 1 , Y 2 , and Y 3 is substituted with —CH 2 SO 3 H,

Z 1 is proline or hydroxyproline, and

wherein the saccharide or polysaccharide comprises one or more sugars selected from the group consisting of:

2-(acetylamino)-2-deoxy-galactose,

galactose,

2-(acetylamino)-2-deoxy-glucose,

fucose, and

5-acetamido-3,5-dideoxy-glycero-galacto-2-nonulosonic acid.

2. The glycopeptide of claim 1 , wherein at least two of Y 1 , Y 2 , and Y 3 are substituted with —CH 2 SO 3 H.

3. The glycopeptide of claim 1 , wherein Y 1 , Y 2 , and Y 3 are substituted with —CH 2 SO 3 H.

4. The glycopeptide of claim 1 , wherein the polysaccharide is sialyl Lewis X or sialyl Lewis A.

5. The glycopeptide of claim 1 , wherein the polysaccharide comprises

2-(acetylamino)-2-deoxy-galactose alpha 1 bonded to W 1 ,

galactose beta 3 bonded to 2-(acetylamino)-2-deoxy-galactose,

2-(acetylamino)-2-deoxy-glucose beta 6 bonded to 2-(acetylamino)-2-deoxy-galactose and

fucose is alpha 3 bonded to 2-(acetylamino)-2-deoxy-glucose.

6. The glycopeptide of claim 1 , wherein the polysaccharide comprises

2-(acetylamino)-2-deoxy-galactose alpha 1 bonded to W 1 ,

galactose beta 3 bonded to 2-(acetylamino)-2-deoxy-galactose,

2-(acetylamino)-2-deoxy-glucose beta 6 bonded to 2-(acetylamino)-2-deoxy-galactose,

fucose is alpha 3 bonded to 2-(acetylamino)-2-deoxy-glucose, and

galactose beta 4 bonded to 2-(acetylamino)-2-deoxy-glucose.

7. The glycopeptide of claim 1 , wherein the polysaccharide comprises

2-(acetylamino)-2-deoxy-galactose alpha 1 bonded to W 1 ,

galactose beta 3 bonded to 2-(acetylamino)-2-deoxy-galactose,

2-(acetylamino)-2-deoxy-glucose beta 6 bonded to 2-(acetylamino)-2-deoxy-galactose,

fucose is alpha 3 bonded to 2-(acetylamino)-2-deoxy-glucose,

galactose beta 4 bonded to 2-(acetylamino)-2-deoxy-glucose, and

5-acetamido-3,5-dideoxy-glycero-galacto-2-nonulosonic acid alpha 3 bonded to galactose.

8. The glycopeptide of claim 1 , wherein the polysaccharide comprises,

2-(acetylamino)-2-deoxy-galactose alpha 1 bonded to W 1 ,

galactose beta 3 bonded to 2-(acetylamino)-2-deoxy-galactose,

2-(acetylamino)-2-deoxy-glucose beta 6 bonded to 2-(acetylamino)-2-deoxy-galactose,

galactose beta 4 bonded to 2-(acetylamino)-2-deoxy-glucose,

5-acetamido-3,5-dideoxy-glycero-galacto-2-nonulosonic acid alpha 3 bonded to galactose, and

fucose is alpha 3 bonded to 2-(acetylamino)-2-deoxy-glucose.

9. The glycopeptide of claim 1 , wherein the polysaccharide comprises,

2-(acetylamino)-2-deoxy-galactose alpha 1 bonded to W 1 ,

a first galactose beta 3 bonded to 2-(acetylamino)-2-deoxy-galactose,

2-(acetylamino)-2-deoxy-glucose beta 6 bonded to 2-(acetylamino)-2-deoxy-galactose,

a second galactose beta 4 bonded to 2-(acetylamino)-2-deoxy-glucose,

fucose is alpha 3 bonded to 2-(acetylamino)-2-deoxy-glucose, and

5-acetamido-3,5-dideoxy-glycero-galacto-2-nonulosonic acid is alpha 3 bonded to the first galactose.

10. The glycopeptide of claim 1 , wherein X 1 , X 3 , X 4 , and X 7 are each individually and independently E, D, N, or Q.

11. The glycopeptide of claim 1 , wherein X 2 , X 5 , and X 6 are each individually and independently L, I, V, A or F.

12. The glycopeptide of claim 1 , wherein the isolated glycopeptide comprises

(SEQ ID NO: 2)

Y 1 EY 2 LDY 3 DFLZ 1 EW 1 ,

(SEQ ID NO: 3)

Y 1 EY 2 LDY 3 DFLZ 1 EW 1 EP,

(SEQ ID NO: 4)

Y 1 EY 2 LDY 3 DFLZ 1 EW 1 EPL,

(SEQ ID NO: 5)

EY 1 EY 2 LDY 3 DFLZ 1 EW 1 ,

(SEQ ID NO: 6)

EY 1 EY 2 LDY 3 DFLZ 1 EW 1 E,

(SEQ ID NO: 7)

EY 1 EY 2 LDY 3 DFLZ 1 EW 1 EP,

(SEQ ID NO: 8)

EY 1 EY 2 LDY 3 DFLZ 1 EW 1 EPL,

(SEQ ID NO: 9)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 ,

(SEQ ID NO: 10)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 E,

(SEQ ID NO: 11)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 EP,

or

(SEQ ID NO: 12)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 EPL.

13. The glycopeptide of claim 1 selected from KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 EPL (SEQ ID NO: 12) or salt thereof wherein,

W 1 is threonine,

Y 1 , Y 2 , and Y 3 are phenylalanine 4-substituted with —CH 2 SO 3 H,

Z 1 is proline,

2-(acetylamino)-2-deoxy-galactose alpha 1 bonded to W 1 ,

galactose beta 3 bonded to 2-(acetylamino)-2-deoxy-galactose, 2-(acetylamino)-2-deoxy-glucose beta 6 bonded to 2-(acetylamino)-2-deoxy-galactose, fucose is alpha 3 bonded to 2-(acetylamino)-2-deoxy-glucose, galactose beta 4 bonded to 2-(acetylamino)-2-deoxy-glucose, and 5-acetamido-3,5-dideoxy-glycero-galacto-2-nonulosonic acid is alpha 3 bonded to galactose.

14. A pharmaceutical composition comprising a glycopeptide of claim 1 and a pharmaceutically acceptable excipient.

15. The pharmaceutical composition of claim 14 in the form of a pill, tablet, capsule, or gel.

16. The pharmaceutical composition of claim 14 in the form of an aqueous saline buffer wherein the pharmaceutically acceptable excipient is a saccharide or polysaccharide.

17. A method of treating or preventing atherosclerosis, atherosclerotic lesions, thrombus formation, thromboembolism, stroke, or myocardial infarction comprising administering an effective amount of a pharmaceutical composition of claim 14 to a subject in need thereof.

18. The method of claim 17 wherein the subject is at risk of, exhibiting symptoms of, or diagnosed with atherosclerosis, atherosclerotic lesions, thrombus formation, thromboembolism, stroke, or myocardial infarction.

19. A method of treating or preventing allergy or lung diseases comprising administering an effective amount of a pharmaceutical composition of claim 14 to a subject in need thereof.

20. The method of claim 17 wherein the subject is at risk of, exhibiting symptoms of, or diagnosed with asthma, bronchitis, emphysema, and COPD.

21. The glycopeptide of claim 1 , wherein the isolated glycopeptide comprises

(SEQ ID NO: 4)

Y l EY 2 LDY 3 DFLZ 1 EW 1 EPL,

(SEQ ID NO: 8)

EY 1 EY 2 LDY 3 DFLZ 1 EW 1 EPL,

(SEQ ID NO: 9)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 ,

(SEQ ID NO: 10)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 E,

(SEQ ID NO: 11)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 EP,

or

(SEQ ID NO: 12)

KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 EPL.

22. The glycopeptide of claim 1 , wherein the isolated glycopeptide comprises KEY 1 EY 2 LDY 3 DFLZ 1 EW 1 EPL (SEQ ID NO: 12).

23. The glycopeptide of claim 22 , wherein W 1 is threonine.

24. The glycopeptide of claim 22 , wherein Z 1 is proline.

Assignments (1)
CONFIRMATORY LICENSE Recorded Jun 14, 2016
From: EMORY UNIVERSITY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 038983/0698 →
Continuity (1)
Related Publication 20160108092A1 · Apr 21, 2016