Highly active polypeptides and methods of making and using the same

• US 9,782,454 B2
• Filed: 04/22/2011
• Issued: 10/10/2017
• Est. Priority Date: 04/22/2010
• Status: Active Grant

• Current Assignee: Longevity Biotech, Inc.
• Original Assignee: Longevity Biotech, Inc.
• Inventors: Shandler, Scott J., Gellman, Samuel H.
• Primary Examiner(s): Alstrum Acevedo, James H
• Assistant Examiner(s): Coffa, Sergio
• Application Number:
  US13/642,757
• Publication Number:
  US 20130096050A1
• Time in Patent Office: 2,363 Days
• Field of Search: None
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides

Abstract

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.

Claims

1. A composition comprising a peptide comprising the amino acid sequence HSDAVFTDNYX₁RLX₂KQLX₁VKX₂YLNX₁ILN (SEQ ID NO:

1346) or a pharmaceutically acceptable salt thereof, wherein X₁ is the beta cyclic amino acid ACPC and X₂ is the beta cyclic amino acid APC, and wherein the peptide comprises at least two contiguous patterns of α and

β

amino acids comprising α

α

β

α

α

α

β

.

2. The composition of claim 1, wherein the peptide has increased selectivity to VPAC1 as compared to its binding to the VPAC2 receptor at the same concentration.

3. The composition of claim 1, further comprising one other active agent.

4. A method of manufacturing the composition of claim 1 or a pharmaceutical salt derived therefrom comprising catalyzing a reaction between at least one α

-amino acid with at least one β

-amino acid of the analog.

5. A method of inhibiting secretion of TNF-α

in a subject or treating pulmonary hypertension, primary arterial hypertension (PAH), pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, high blood pressure, CREST syndrome-Calcinosis, Raynaud'"'"'s disease, loss of muscle control of the Esophagus, Sclerodactyly, Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung'"'"'s Disease, sexual dysfunction, erectile dysfunction, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, elevated blood pressure levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren'"'"'s syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof comprising administrating the composition of claim 1, or a pharmaceutical salt derived therefrom, to the subject in need thereof.

6. A kit comprising the composition of claim 1.

7. The kit of 6, wherein a first container comprises the composition and a second container comprises a vehicle for administration of the composition.

8. A composition comprising a peptide comprising an amino acid sequence that is at least 96% homologous to HSDAVFTDNYX₁RLX₂KQLX₁VKX₂YLNX₁ILN (SEQ ID NO:

1346) or a pharmaceutically acceptable salt thereof, wherein X₁ is the beta cyclic amino acid ACPC and X₂ is the beta cyclic amino acid APC, and wherein the peptide comprises at least two contiguous patterns of α and

β

amino acids comprising α

α

β

α

α

α

β

.

9. The composition of claim 8, wherein the peptide has increased selectivity to the VPAC2 as compared to its binding to the VPAC1 receptor at the same concentration.

10. The composition of claim 8, further comprising one other active agent.

11. A method of manufacturing the composition of claim 9, or a pharmaceutical salt derived therefrom, comprising catalyzing a reaction between at least one α

-amino acid with at least one β

-amino acid of the analog.

12. A kit comprising the composition of claim 8.