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Methods and compositions related to improving properties of pharmacological agents targeting nervous system

A composition and technology for neurological disorders, applied in chemical instruments and methods, polypeptides containing positioning/targeting motifs, pharmaceutical formulations, etc.

Inactive Publication Date: 2009-06-03
UNIV OF UTAH RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of the available peptide engineering techniques have been applied to neuropeptides with anticonvulsant activity

Method used

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  • Methods and compositions related to improving properties of pharmacological agents targeting nervous system
  • Methods and compositions related to improving properties of pharmacological agents targeting nervous system
  • Methods and compositions related to improving properties of pharmacological agents targeting nervous system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0341] 1. Example 1: Anticonvulsant galanin analogs with systemic activity

[0342] To obtain proof-of-concept results that anticonvulsant neuropeptides can be engineered to enhance their blood-brain barrier penetration, two neuropeptides were selected: somatostatin and galanin. As mentioned above, both neuropeptides mentioned above have anticonvulsant activity.

[0343] The overall experimental method is Figure 7 shown in . A panel of neuropeptide analogs (generation 1) was designed and synthesized to test their ability to bind their respective receptors with high affinity. The panel included about 10 analogs of each neuropeptide. The high affinity analogs were further tested for their ability to penetrate the blood brain barrier. After the results of the first generation analogs were obtained and the second generation analogs were synthesized and evaluated, then the third generation analogs. The most promising analogs (high-affinity ligands with enhanced blood-brain ba...

Embodiment 2

[0389] 2. Example 2: Anticonvulsant Galanin Analogs

[0390] Galanin is a 30 amino acid neuropeptide, the N-terminal portion of which is still a very potent agonist compared to the full-length peptide (Langel and Bartfai, 1998). A truncated analog of galanin (1-16) (described below) was used to introduce modifications that enhance its permeability across the blood-brain barrier.

[0391] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

[0392] Gly Trp Thr Leu Asn Ser Ala Gly Tyr Leu Leu Gly Pro His Ala Val

[0393] The following residues critical for biological activity were identified: Gly 1 、Trp 2 、Asn 5 、Tyr 9 and Gly 12 (Land et al., 1991). Such N-terminal extensions or truncations result in loss of biological activity. On the other hand, galanin (1-16) is very robust when its C-terminal part is truncated or linked to a larger structure (Pooga et al., 1998).

[0394] Based on the available structure-activity relationship data, two peptide-based galanin analogs were designed,...

Embodiment 3

[0434] 3. Example 3: GAL-BBB2 has effective pain relief effect

[0435] a) Formaldehyde solution test

[0436] A 0.5% formaldehyde solution was injected into the plantar region of the mouse's right hind paw. This induced a distinctly different pattern of biphasic behavior characterized by mice licking the diseased paw. Immediately after injection, mice lick their paws for approximately 10 minutes. This is Phase 1 (acute), followed by a short latency period during which there is little behavioral activity. This is followed by a longer paw licking phase of about 20 to 30 minutes which constitutes phase 2 (inflammatory).

[0437] Before administration of the active peptide, drug, or vehicle, each mouse underwent a 15-minute conditioning period in one of several 6" tall Plexiglas observation tubes (4" diameter) in which The tube is placed in front of a mirror. Following the conditioning period, mice were treated with an intraperitoneal injection of GAL-BBB2 (the inactive natu...

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Abstract

The present invention discloses compositions and methods related to improving pharmacological properties of bioactive compounds targeting nervous system.

Description

[0001] Cross references to related patent applications [0002] This application claims the benefit of US Provisional Application Serial No. 60 / 757,047, filed January 5, 2006, and US Provisional Application Serial No. 60 / 844,024, filed September 11, 2006. US Provisional Application Serial No. 60 / 757,047, filed January 5, 2006, and US Provisional Application Serial No. 60 / 844,024, filed September 11, 2006 are hereby incorporated by reference in their entireties. Background technique [0003] The blood-brain barrier (BBB) ​​separates the mammalian brain from the systemic circulation and plays a crucial role in central nervous system (CNS) homeostasis. Despite continuous progress in understanding the transport of peptides across the blood-brain barrier, how to efficiently deliver them directly into the CNS remains a major challenge in the development of neuropeptides as potential therapeutic agents. [0004] For example, epilepsy is a complex neurological disorder. It is estima...

Claims

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Application Information

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IPC IPC(8): A61K38/00
CPCC07K5/1019C07K7/06C07K7/23C07K14/575C07K14/57545C07K14/6555C07K14/665C07K2319/01C07K7/08C07K14/47
Inventor G·布利S·H·怀特
Owner UNIV OF UTAH RES FOUND
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