Cyclic galanin analogs and uses thereof

A cyclic analog, galanin technology, applied in the field of medicine and pharmacy, can solve the problem of reduced agonist specificity

Active Publication Date: 2021-11-12
LANTHIO PEP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of safety, it appears that the agonistic specificity for GalR2 and decreased agonistic specificity for GalR3 may be related

Method used

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  • Cyclic galanin analogs and uses thereof
  • Cyclic galanin analogs and uses thereof
  • Cyclic galanin analogs and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0294] Example 1: Synthetic lambulfine - stabilized glypropanole analog (wool sulfur-glyproprine)

[0295] A glyproprine variant containing woolliternine is prepared according to the established method, for example, as described in the following literature: Kluskens 2005Post-Translational Modification of the Dehydrats of the lantibiotic nisin.biochemistry 44,12827 12834; Kluskens2009angiotensin- (1-7) with thioether-bridge: analogue.j.pharmacol.exper.j.pharmacol.exper.ther.328,849-854; rink 2007c Nisc, The Cyclase Offe Lantibiotic Nisin .,.

[0296] Briefly, lactococcus lactis includes two plasmid systems. The first plasmold coded antibiotic niobin (NISIN) preopeptide MSTKDFNLDLVSVSKDSGASPR, and its C-terminus and the objective in (meth) wool thikine-glyproprine precursor peptide fusion The above peptide contains serine / threonine at position [i], and has a cysteine ​​at position [i + 3], [i + 4] or [I + 5]. Plasmids encoding a fusion peptide comprising a NiS precondition sequen...

Embodiment 2

[0299] Example 2: Activity of Wool Sulfide - Stabilized Glycopropeptide (Wool Sulfur - Glyceride)

[0300] (Wool sulfur) glyprotinin biologically active was determined in the CHO-K1 cell line expressing GALR1 or GALR2 receptor. Active measurements were carried out using commercial kits for assaying inhibitory protein recruits (GALR1, GALR2) and CAMP synthesis inhibition (GALR1) for assaying inhibitory proteins. In addition, the HEK293 cell line expressing the GALR2 receptor has been used to measuring calcium flow (GALR2).

[0301]

[0302]

[0303]

[0304] result

[0305] The results are summarized in Table 1. The numerical value refers to an EC50 of an analog to which the expression observed with a linear glycetin (1-15) set to the value of 1.0. ND refers to "not determined".

[0306] Surprisingly, it is discovered that (meth) wool hydrazine is introduced into the C-terminal of glyproprine so that the direction towards the GALR2 tend to migrate. Specifically, GALM50B, GA...

Embodiment 3

[0310] Chemical synthetic lanamine thiramine thiramine thiopartide is extruded by base-assisted sulfur sulfur to obtain glyproprine.

[0311] Ordering two peptides in Pepscan as raw materials:

[0312] 1) SYM-4178: H-Qwnlnaagyllgpcavc-oh

[0313] The peptide is related to GALM87. However, although biosynthetic Galm87 may contain D, L wool thiternine, chemical synthesis results in an or more isomer. Interestingly, one of the isomers containing wool thionic isomers (Table 2) have high activity.

[0314] 2) SYM-4179: H-QWTLNAACYLLC-OH

[0315] The peptide is related to GALM82 (Table 1). However, although biosynthetic Galm82 may contain D, L wool thiosine, chemical synthesis results in one or more isomers. More interesting is that one of these 4179b (Table 2) seems to have high activity.

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Abstract

The present invention relates generally to the fields of medicine and pharmacy. More specifically, it relates to novel galanin analogs and their use in therapy. The present invention provides cyclic peptide analogs of galanin, wherein the galanin analog comprises a (methyl)lanthionine bridge, and wherein the analog has the general formula "X1-X2-X3-X4-X5-X6- X7‑X8‑X9‑X10‑X11‑X12‑X13‑X14‑X15‑X16‑X17‑X18‑X19‑X20‑X21‑X22‑", or its lack of X1 and / or up to 11 C-terminal residues A truncated variant wherein two residues selected from X3, X4, X6, X7, X10 and X13-X19 together form a lanthionine bridge of the structure Ala-S-Ala or the structure Abu-S-Ala or Ala ‑S‑Abu's methyllanthionine bridge.

Description

Technical field [0001] The present invention generally relates to medical and pharmaceutical fields. More specifically, it relates to novel galanin analogs, their preparation and their use in therapy. Background technique [0002] Galanin is a 29-30 neuropeptide consisting of a chain of amino acids, which is encoded by a GAL gene called front body galanin original protein cleavage (preprogalanin) produced 123 amino acids. Galanin is widely expressed in human and other mammalian brain, spinal cord and intestine. Galanin involves many different biological function, comprising: nociception, regulate wakefulness and sleep, cognition, regulation of food intake, mood regulation, blood pressure regulation, it also plays a role in the development of, and factors play a role in nutrition . Galanin and many kinds of diseases, including Alzheimer's disease, epilepsy and depression, eating disorders and cancer. [0003] Galanin receptor subtypes stimulating three kinds of GalR1, GalR2 and Ga...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00A61K38/22A61K47/64A61P25/28A61P25/22A61P25/24A61P25/08A61P25/00A61P1/04
CPCC07K2319/02C07K2319/50C07K14/575A61K38/22A61P1/04A61P25/00A61P25/08A61P25/22A61P25/24A61P25/28A61P43/00C07K7/64A61K38/00A61K47/549C07K1/04C07K1/1075
Inventor A·奎伯斯
Owner LANTHIO PEP
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