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Dimeric thrombopoietin peptide mimetics binding to MP1 receptor and having thrombopoietic activity

A technology of receptor binding and compounds, applied in the field of compounds, can solve problems such as lack of sequence homology

Inactive Publication Date: 2001-12-05
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 14-group peptide, named TMP (TPO Mimetic Peptide), has no significant sequence homology to TPO or MGDF

Method used

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  • Dimeric thrombopoietin peptide mimetics binding to MP1 receptor and having thrombopoietic activity
  • Dimeric thrombopoietin peptide mimetics binding to MP1 receptor and having thrombopoietic activity
  • Dimeric thrombopoietin peptide mimetics binding to MP1 receptor and having thrombopoietic activity

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[0098] Lysine and amino terminal residues can be reacted with succinic acid or other carboxylic anhydrides. The effect of derivatization reactions with these reagents is to reverse the charge of the lysine residues. Other suitable reagents for derivatizing residues containing α-amino groups include: imidate such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroboration trinitrobenzenesulfonic acid; O-methylisourea; 2,4-pentanedione; and transaminase-catalyzed reactions with glyoxylate.

[0099]Arginine residues can be modified by reaction with one or several conventional reagents, including phenylacetaldehyde, 2,3-butanedione, 1,2-cyclohexanedione, and ninhydrin. The derivatization of arginine residues requires basic conditions due to the high pKa of the guanidine functional group. Furthermore, these reagents react with both lysine and arginine guanidine groups.

[0100] The specific modification of tyrosine residues has been intensively studied, with particu...

Embodiment

[0237] Ⅰ. Examples of preparation methods for some of the first group of compounds disclosed herein will be described below.

[0238] A. Materials and Methods

[0239] All amino acid derivatives (all in L configuration) and resins used in peptide synthesis were purchased from Novabiochem. Peptide synthesis reagents (DCC, HOBt, etc.) were purchased from Applied Biosystems, Inc. in solution. Both PEG derivatives were purchased from Shearwater Polymers, Inc. All solvents (dichloromethane, N-methylpyrrolidone, methanol, acetonitrile) were purchased from EM Sciences. HPLC analysis was performed on a Vydac column (0.46cm×25cm, C18 reverse phase, 5mm) of the Beckman system with an elution flow rate of 1 ml / min and dual UV detection at 220 and 280 nm. A linear gradient of two mobile phases, buffer A-water (0.1% TFA) and buffer B-acetonitrile (0.1% TFA) was used in all HPLC runs. The numbered peptides cited here, such as 17b, 18, 19 and 20, may be referred to in Table 1 for numer...

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Abstract

The invention relates to the field of compounds, especially peptides or polypeptides, that have thrombopoietic activity. The peptides and polypeptides of the invention may be used to increase platelets of platelet precursors (e.g., megakaryocytes) in a mammal.

Description

[0001] This application claims priority to US Provisional Application 06 / 105,348, filed October 23, 1998. field of invention [0002] Basically, the present invention relates to the field of compounds, in particular peptides or polypeptides having thrombopoietic activity. The peptides or polypeptides of the present invention can be used in mammals to increase the production of platelets or platelet precursors such as megakaryocytes. Background of the invention [0003] The present invention relates to the field of compounds, particularly peptides having the ability to stimulate the production of platelets and their precursors, such as megakaryocytes, in vitro and in vivo. Before discussing the properties of the compounds of the present invention, two proteins with thrombopoietic activity: thrombopoietin (TPO) and megakaryocyte growth and development factor (MGDF) are provided as background information below. [0004] Cloning o...

Claims

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Application Information

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IPC IPC(8): C12N15/09A61K38/00A61P7/00C07K14/52C07K19/00C12N1/15C12N1/19C12N1/21C12N5/10C12P21/02
CPCC07K7/08C07K14/524C07K2319/00C07K7/06A61K38/00C07K2319/30A61P43/00A61P7/00A61P7/04A61P7/06C07K14/52C07K2319/75
Inventor C·-F·刘U·菲格J·奇塔姆
Owner AMGEN INC
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