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Improved apo e analogs and methods for their use

A technology of analogs, drugs, applied in improved APOE analogs and their fields of use, which can solve problems such as exacerbation, sepsis, elevation, etc.

Inactive Publication Date: 2007-12-05
CORNERSTONE THERAPEUTICS (SHANGHAI) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In particular, Hong et al. (1995) reported that tumor necrosis factor α (TNFa), interleukin 1α and 1β (IL1a and IL1b) significantly elevated mRNA at a dose that caused less than 10% of deaths
Despite the beneficial effects of ApoE on innate immunity, as evidenced by the fact that ApoE-deficient mice lack innate immunity to systemic infection leading to sepsis and severe exacerbations, the role of ApoE in intestinal inflammation remains incomplete. clarify

Method used

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  • Improved apo e analogs and methods for their use
  • Improved apo e analogs and methods for their use
  • Improved apo e analogs and methods for their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0211] Example 1: Design and Characterization of Improved Peptide Analogs

[0212] Retro Inverso Peptide

[0213] Peptide analogs containing substitutions with D-amino acids for L-amino acids were prepared to study the stereospecificity of ApoE 130-150 activity. Applicants compared all L-amino acid peptides to all D-amino acid peptides to test whether retro-inverso analogs of ApoE 130-150 were active. The retro-inverso analogue is the reverse sequence (ie ApoE 150-130), which consists only of D-amino acids (all D ApoE 150-130). Unlike the report by Pescarolo et al. (2001), the applicants found that the retro-inverso peptide was incredibly toxic at any concentration above 0.01 micromolar. Therefore, the observed marked reduction in nitric oxide production by BV-2 microglia is an artifact since the cells tested had been killed by this retro-inverso peptide. Furthermore, all-D amino acid analogues of ApoE 130-150 did not have the activity to inhibit the release of nitric oxide...

Embodiment 2

[0288] Example 2: Characterization of COG432

[0289] Figure 4 presents the rotarod test results after TBI treated with 4 mg / kg or 1 mg / kg of COG432, (COG432: Ac-ASHLRKLAibKRLL (SEQ ID NO. 6)) or control (saline). The vertical axis is rotarod balance performance (100% is rotarod balance performance prior to TBI). Treatment with COG432 4 mg / kg or saline was initiated 2 hours after traumatic brain injury and animals were tested beginning day 1 post-TBI and daily for 5 days thereafter. On day 5 post-TBI, animals treated with 4 mg / kg of COG432 peptide recovered approximately 80% of their function as determined by the rotarod test. Control mice treated with saline vehicle alone recovered less than 50% of their function.

Embodiment 3

[0290] Example 3: Characterization of COG1410

[0291] COG1410 was synthesized, an analog containing two aminobutyric acid (Aib) substitutions at positions L140 and R145. Aib is an unnatural amino acid that has been found to form a helical conformation independent of the type of amino acid in the peptide (Marshall et al. 1990). Furthermore, Aib increases binding affinity as it exhibits a reduced loss of conformational entropy upon binding relative to other amino acids (Ratnaparkhi et al. 2000).

[0292] Cellular level analysis

[0293] As shown in Figure 7, we found that COG1410 was significantly more potent than COG133 when tested at the cellular level to inhibit the release of nitric oxide (9A) and TNFa (9B). Furthermore, preliminary in vivo screening suggested that COG1410 was neuroprotective when administered 120 minutes after TBI, in contrast COG133 was not neuroprotective at this time point (Figure 8).

[0294] Dose-response study

[0295] Preliminary dose-response s...

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Abstract

Novel ApoE peptide derivatives and ApoE-protein transduction domain conjugates are disclosed which are useful for treating disorders including CNS inflammation, traumatic brain injury, inflammatory bowel disease (also known as Crohn's Disease or ulcerative colitis), cerebral ischemia, atherosclerosis, sepsis, multiple sclerosis and arthritic diseases, Alzheimer's Disease and other brain disorders. The invention encompasses methods for protecting subjects having undergone irradiation or radiotherapy by administration of ApoE or at least one ApoE mimetic peptide.

Description

[0001] 1. Cross references to related applications [0002] This application claims priority to provisional applications 60 / 606,506, filed September 2, 2004, 60 / 608,148, filed September 9, 2004, and 60 / 606,507, filed September 2, 2004, at This application is hereby incorporated by reference in its entirety into the present application. This application is also related to applications 09 / 260,430 filed March 1, 1999, 09 / 957,909 filed September 21, 2001, 10 / 252,120 filed September 23, 2002, and March 29, 2005 Filed application 11 / 091,336, which is hereby incorporated by reference in its entirety into this application. 2. Technical field [0003] The present invention relates to compounds and compounds useful in the treatment of traumatic brain injury, inflammatory bowel disease (IBD), Crohn's Disease, ulcerative colitis, arthritis, multiple sclerosis, atherosclerosis, and sepsis method. The invention also relates to methods of protecting subjects against the effects of radiati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00
CPCA61K38/1709C07K14/775A61P1/00A61P1/02A61P1/04A61P11/04A61P13/10A61P17/02A61P17/06A61P17/16A61P19/02A61P25/00A61P25/02A61P25/28A61P29/00A61P31/04A61P37/02A61P39/00A61P43/00A61P9/00A61P9/10Y02A50/30
Inventor 迈克尔·P·维特克苏珊·E·麦克纳
Owner CORNERSTONE THERAPEUTICS (SHANGHAI) LTD
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