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Ester-based peptide prodrugs

a peptide and prodrug technology, applied in the field of peptide-based prodrugs, can solve the problems of life-threatening hypoglycemia, extremely difficult to normalize blood glucose without occurrence of hypoglycemia, and demonstrated unparalleled ability to lower glucose in virtually all cases

Inactive Publication Date: 2011-03-17
INDIANA UNIV RES & TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for creating prodrug derivatives of bioactive polypeptides by covalently linking a dipeptide to the polypeptide through an ester linkage. The dipeptide is designed to interfere with the polypeptide's ability to interact with its receptor or cofactor. The prodrug is then cleaved to restore full activity to the polypeptide. The patent also describes the structure of the prodrug and provides various examples of how it can be used. The technical effect of this invention is to provide a way to create a stable prodrug that can be selectively cleaved to restore full activity to the polypeptide.

Problems solved by technology

It demonstrates unparalleled ability to lower glucose in virtually all forms of diabetes.
Unfortunately, its pharmacology is not glucose sensitive and as such it is capable of excessive action that can lead to life-threatening hypoglycemia.
Inconsistent pharmacology is a hallmark of insulin therapy such that it is extremely difficult to normalize blood glucose without occurrence of hypoglycemia.
One disadvantage associated with the therapeutic use of these three peptides is their extremely short half-life (approximately two minutes) in plasma.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

embodiments

[0136]The present disclosure describes the formulation of prodrug derivatives of known bioactive polypeptides. More particularly, the prodrugs disclosed herein are formulated to enhance the half life of the parent bioactive peptide or protein, while allowing for activation of the prodrug via a non-enzymatic degradation mechanism. The ideal prodrug should be soluble in water at physiological conditions (for example, a pH of 7.2 and 37° C.), and it should be stable in the powder form for long term storage. It should also be immunologically silent and exhibit a low activity relative to the parent drug. Typically the prodrug will exhibit no more than 10% of the activity of the parent drug, in one embodiment the prodrug exhibits less than 10%, less than 5%, about 1%, or less than 1% activity relative to the parent drug. Furthermore, the prodrug, when injected in the body, should be quantitatively converted to the active drug within a defined period of time. As disclosed herein, applicant...

example 1

Synthesis of glucagon and GLP-1 analogs

[0980]To investigate the possibility of preparing prodrugs derivative of glucagon and GLP-1, numerous peptide analogs were synthesized. The standard procedure is described briefly here and in FIGS. 3 and 4, and the details are discussed later.

[0981]Materials:

[0982]PAM resin (PAM resin is OCH2-phenylacetamidomethyl-copolystyrene-1% divinylbenzene), (100-180 mesh, 1% DVB cross-linked polystyrene; loading of 0.7-10 mmol / g), Boc-protected and Fmoc protected amino acids were purchased from Midwest Biotech. Other reagents such as the α-hydroxy-acids (phenyllactic acid and glycolic acid) were purchased from Aldrich. The solid phase peptide syntheses using Boc-protected amino acids were performed on an Applied Biosystem 430A Peptide Synthesizer. Fmoc protected amino acid synthesis was performed using the Applied Biosystems Model 433 Peptide Synthesizer. The manual synthesis of depsi-peptides was performed in sintered reaction vessels using analogous pr...

example 2

[1008]Bioassay Experimental Design: Luciferase-Based Reporter Gene Assay for cAMP Detection

[1009]The ability of each glucagon and GLP-1 analog or prodrug to induce cAMP was measured in a firefly luciferase-based reporter assay. The cAMP production that is induced is directly proportional to the glucagon or GLP-1 binding to its receptor. HEK293 cells co-transfected with the glucagon or GLP-1 receptor, respectively, and luciferase gene linked to a cAMP responsive element were employed for the bioassay.

[1010]The cells were serum-deprived by culturing 16 hours in Dulbecco Minimum Essential Medium (Invitrogen, Carlsbad, Calif.) supplemented with 0.25% Bovine Growth Serum (HyClone, Logan, Utah) and then incubated with serial dilutions of either GLP-1 analogs or prodrugs for 5 hours at 37° C., 5% CO2 in 96 well poly-D-Lysine-coated “Biocoat” plates (BD Biosciences, San Jose, Calif.). At the end of the incubation, 100 μL of LucLite luminescence substrate reagent (Perkin Elmer, Wellesley, Ma...

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Abstract

Prodrug formulations of bioactive polypeptides are provided wherein the bioactive polypeptide has been modified by the linkage of a dipeptide to the bioactive polypeptide through an ester linkage. The prodrugs disclosed herein in some embodiments have extended half lives of at least 1.5 hours (e.g., at least 10 hours), and more typically greater than 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Description

BACKGROUND[0001]Peptide-based drugs are highly effective medicines with relatively short duration of action and variable therapeutic index. The present disclosure is directed to peptide-based prodrugs wherein the prodrug derivative is designed to delay onset of action and extend the half life of the drug. The delayed onset of action is advantageous in that it allows systemic distribution of the prodrug prior to its activation. Accordingly, the administration of prodrugs eliminates complications caused by peak activities upon administration and increases the therapeutic index of the parent drug.[0002]Receptor recognition and subsequent processing of the peptide and protein agonists is the primary route of degradation of many peptide and protein-based drugs. Thus binding of the peptide drug to its receptor will result in biological stimulation, but will also initiate the subsequent deactivation of the peptide / protein induced pharmacology through the enzymatic degradation of the peptid...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/26C07K14/605A61P3/10A61P3/00A61P1/00
CPCA61K9/0019A61K38/26A61K39/395A61K47/48215A61K47/48246A61K38/28A61K47/60A61K47/64A61P1/00A61P3/00A61P3/04A61P3/08A61P3/10A61P43/00
Inventor DIMARCHI, RICHARD D.DE, ARNAB
Owner INDIANA UNIV RES & TECH CORP
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