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Isoform-specific calpain inhibitors, methods of identification, and uses thereof

An excipient, pharmaceutical technology, applied in the field of isotype-specific calpain inhibitors and their identification and use, can solve the problem of not creating inhibitors and the like

Inactive Publication Date: 2017-08-04
WESTERN UNIV OF HEALTH SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While the literature has described inhibitors with some degree of selectivity for calpain-2 over calpain-1, and vice versa, no inhibitors with specific substrate benefits have been created until now

Method used

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  • Isoform-specific calpain inhibitors, methods of identification, and uses thereof
  • Isoform-specific calpain inhibitors, methods of identification, and uses thereof
  • Isoform-specific calpain inhibitors, methods of identification, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Example 1 Small Molecules / Modified Polypeptides with High Selectivity for Calpain-2

[0179]

[0180] Formula 1, in which chiral center 1 is the L-form and in which chiral center 2 is a racemic mixture of D- and L-, was introduced in vitro at different concentrations (from 1 nM to 10 μM) mixed, including succinyl-leucine-tyrosine-AMC and calpain-1 or calpain-2 (Sasaki et al., 1984), and the kinetics of fluorescence loss for each calpain was determined (Powers et al., 2000 ). The Ki values ​​of the compounds obtained in the literature are 2.3 μM for calpain-1 and 0.22 μM for calpain-2 (Li et al., 1996). However, the present inventors re-determined the Ki of calpain-1 as 1.29 μM±0.7 μM and the Ki of calpain-2 as 0.025 μM±0.02 μM. Accordingly, the selectivity assessment described herein differs from previous teachings. This compound is a highly selective inhibitor of calpain-2 as its Ki for calpain-2 is more than 50 times lower than the Ki for calpain-1.

Embodiment 2

[0181] Example 2: Universal calpain inhibitors block LTP when administered prior to LTP induction. Excitatory postsynaptic potentials (EPSP, figure 2 ) field records. 10 μM calpain inhibitor III (Z-Val-Phe-CHO, with a Ki of about 8 nM for calpain-1 and calpain-2), which inhibits both calpain-1 and calpain-2, was stimulated by theta rhythm ( TBS, 10 rhythms of 4 pulses at 100 Hz with a rhythm interval of 200 ms) was added before, which can be used to elicit LTP (Capocchi et al., 1992). When compared to control (compare open and filled circles), pre-incubation of a non-selective calpain inhibitor (calmodulinase inhibitor III) did not prevent short-term potentiation (increased fEPSPs after TBS), but prevented LTP formation .

Embodiment 3

[0182] Example 3: Calpain 2-selective inhibitors enhance LTP. Acute hippocampal slices were prepared and soaked in ACSF. After being able to induce LTP (see Figure 3A 200 nM of the calpain-2 selective inhibitor of formula 1, which is 50-100 times more inhibiting of calpain-2 than calpain-1, was administered prior to theta-rhythmic stimulation of time-dependent administration of line #1. In contrast to the unexpected administration of non-selective calpain inhibitors such as calpain inhibitor III, pre-incubation with calpain-2 selective inhibitor pre-incubation did not inhibit LTP ( Figure 3A ); instead, LTP is enhanced. Incubation of hippocampal slices with the same highly selective calpain-2 inhibitor after theta-rhythmic stimulation (TBS) also resulted in an increase in LTP during the TTP immobilization phase when administered from 10 min post-TBS to 1 hr post-TBS.

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Abstract

Molecules that selectively inhibit or stimulate the activity of isoforms of calpains are presented. Methods for screening and characterizing such molecules are also presented. Specific functions of calpain-1 calpain-2 in long term potentiation (LTP), learning and memory, neurodegeneration and diseases of synaptic dysfunction are characterized using novel calpain inhibitors, substrates and related methods. The compounds, compositions, and methods described herein are expected to be useful, for treating neurodegenerative diseases and other diseases of synaptic function, and for modulating cognition in patients in need thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Patent Application Serial No. 62 / 078221, filed November 11, 2014, the disclosure of which is incorporated herein by reference. technical field [0003] The present invention relates to products that inhibit the function of calpain-1 or calpain-2 and methods for identifying the products, as well as methods for specifically inhibiting the activation or activity of calpain-1 or calpain-2 or for activating calpain-1, and Concerning methods of treating and preventing diseases susceptible to molecular therapy that interferes with the function of calpain-1 or calpain-2, or activates or increases the activity of calpain-1. Background technique [0004] Generic calpain inhibitors and their use to treat disease have not been successful as therapeutic agents (Donkor, 2011, incorporated herein by reference). In the present invention, evidence is provided for the specific use of calpain-2 sel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K38/05A01N57/00
CPCA61P25/00A61P27/06A61K38/06A61P25/08
Inventor M·博德里X·毕S·斯坦德利L·罗Y·王G·朱V·布里斯
Owner WESTERN UNIV OF HEALTH SCI
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