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Methods of using retro-inverso peptides derived from interleukin-3

a technology of retro-inverso peptides and interleukin-3, which is applied in the direction of peptide/protein ingredients, drug compositions, extracellular fluid disorders, etc., can solve the problems of peptides being easily damaged by proteolytic degradation and their biological activity being often greatly compromised

Inactive Publication Date: 2007-03-08
WRIGHT DAVID E +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a retro-inverso peptide that can be used to promote neurite outgrowth or myelination in a mammal. The peptide has a specific sequence that is reversed compared to a naturally occurring peptide. The peptide can be modified by replacing certain amino acids with different ones, adding or replacing carboxylic acid groups, or modifying amino acids with different charges. The peptide can also be glycosylated or esterified. The invention also provides a method for administering the peptide to a mammal to promote neurite outgrowth or myelination. The peptide can be used to stimulate hematopoiesis, resulting in the generation and differentiation of various types of blood cells."

Problems solved by technology

A major obstacle to the in vivo therapeutic use of peptides is their susceptibility to proteolytic degradation.
Although such retro-inverso analogs exhibit increased metabolic stability, their biological activity is often greatly compromised (Guichard et al., Proc. Natl. Acad. Sci. U.S.A.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Stimulation of Neurite Outgrowth

[0037] NS20Y neuroblastoma cells are grown in DMEM containing 10% fetal calf serum (FCS). Cells are removed with trypsin and plated in 30 mm petri dishes onto glass coverslips. After 20-24 hours, the medium is replaced with 2 ml DMEM containing 0.5% FCS plus 0, 0.5, 1, 2, 4 or 8 ng / ml of a RI IL-3-derived peptide having between 12 and about 40 amino acids and including the sequence that is retro-inverso with respect to SEQ ID NO: 1. Cells were cultured for an additional 24 hours, washed with PBS and fixed with Bouin's solution (saturated aqueous picric acid / formalin / acetic acid 15:5:1) for 30 minutes. Fixative was removed with PBS and neurite outgrowth was scored under a phase contrast microscope. Cells exhibiting one or more clearly defined neurites equal to or longer than one cell diameter were scored as positive. At least 200 cells were scored in different portions of each dish to determine the percentage of neurite bearing cells and assays were p...

example 2

Prevention of cell Death

[0038] NS20Y cells are plated as described in Example 1 and grown on glass coverslips in 0.5% fetal bovine serum for 2 days in the presence or absence of 8 ng / ml of an RI IL-3-derived peptide having between 12 and about 40 amino acids and including the sequence that is retro-inverso with respect to SEQ ID NO: 1. Media is removed and 0.2% trypan blue in PBS is added to each well. Blue-staining dead cells are scored as a percentage of the total on an inverted microscope, counting 400 cells in four areas of each well. The average error of duplicates was 5%.

example 3

Promotion of Neurite Outgrowth Ex Vivo

[0039] Dorsal root ganglia are removed from adult rats and sensory neurons were prepared as described by Kuffler et al. (J. Neurobiol. 25:1267-1282, 1994). Neurons are treated with 0.5 ng / ml of an RI IL-3-derived peptide having between 12 and about 40 amino acids and including the sequence that is retro-inverso with respect to SEQ ID NO: 1. After three days of treatment, the length of the longest neuritic projections are measured on a micrometer grid. The longest neurites in neurons treated with RI peptide are approximately three times longer than those treated with a control (non-RI) peptide or in untreated controls. After a 48 hour treatment, all cells respond similarly to nerve growth factor (NGF) in that extensive branching is observed. These results indicate that the IL-3-derived peptides promote the differentiation of sensory neurons.

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Abstract

The invention provides methods of treatment using retro-inverso peptides derived from interleukin-3 (IL-3) having between 12 and about 40 amino acids and including the sequence that is retro-inverso with respect to SEQ ID NO: 1. These peptides of the invention have the same activity as native IL-3 and also have neurotrophic activity. The peptides of the invention are also less susceptible to proteolytic degradation in vivo because of their D-amino acid linkage.

Description

[0001] This application is a continuation of U.S. patent application Ser. No. 10 / 048,302, filed May 7, 2002, which is a national phase application of International Patent Application No. PCT / US00 / 16759, filed Jun. 16, 2000, which claims priority to U.S. Provisional Patent Application No. 60 / 139,688 filed on Jun. 16, 1999, each of which is expressly incorporated herein in its entirety by reference thereto.FIELD OF THE INVENTION [0002] The present invention relates to retro-inverso peptides derived from interleukin-3 (IL-3). These peptides have activities similar to that of the native parent protein, and also have neurotrophic activity. BACKGROUND OF THE INVENTION [0003] Cytokines are proteins which are produced during the effector phases of natural and specific immunity and serve to mediate and regulate immune and inflammatory responses. Cytokines, like other polypeptide hormones, initiate their action by binding to specific receptors on the surface of target cells. One of the most w...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61K38/10
CPCC07K14/5403A61K38/10A61P25/00A61P43/00
Inventor WRIGHT, DAVID E.PARKS, D. ELLIOTT
Owner WRIGHT DAVID E
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