CN-122005576-A - Application of asparaginyl endopeptidase inhibitor in preparation of medicine for improving insulin resistance

CN122005576ACN 122005576 ACN122005576 ACN 122005576ACN-122005576-A

Abstract

The application relates to application of an asparagine endopeptidase inhibitor in preparing a medicament for improving insulin resistance. The application starts from inhibiting the aging driving factor AEP, and the AEP inhibitor is applied to the study of insulin resistance for the first time, and the AEP inhibitor is found to be capable of remarkably improving glucose tolerance and insulin sensitivity. Accordingly, the present application provides the use of an asparagine endopeptidase inhibitor in the manufacture of a medicament for improving insulin resistance. Proved by experiments, the AEP inhibitor not only remarkably enhances insulin sensitivity of old mice and improves glucose tolerance, but also reduces serum low density lipoprotein cholesterol and lactate dehydrogenase level, shows multiple improving effects on glucose metabolism and lipid metabolism, and has no obvious toxic or side effect in blood convention, urine convention and heart, liver, spleen, lung, kidney and other important organ pathology examination after long-term administration, thus proving that the AEP inhibitor has good safety and is suitable for long-term intervention of chronic diseases.

Inventors

YANG MENGHAN
YE KEQIANG

Assignees

中国科学院深圳先进技术研究院

Dates

Publication Date: 20260512
Application Date: 20260327

Claims (10)

1. Use of an asparaginyl endopeptidase inhibitor for the preparation of a medicament for improving insulin resistance.
2. The use according to claim 1, wherein the asparagine endopeptidase inhibitor has the structural formula (I): Formula (I).
3. Use of an asparaginyl endopeptidase inhibitor for the preparation of a medicament for enhancing insulin sensitivity and/or for regulating glucose tolerance.
4. The use according to claim 3, wherein the medicament is further capable of reducing the level of at least one of low density lipoprotein, cholesterol and lactate dehydrogenase.
5. Use of an asparaginyl endopeptidase inhibitor for the preparation of a medicament for the prevention or treatment of metabolic diseases.
6. The use according to claim 5, wherein the metabolic disease is an age-related metabolic disease; further, the metabolic disease includes insulin resistance caused by natural aging.
7. The use according to any one of claims 3 to 6, wherein the asparaginyl endopeptidase inhibitor has the structural formula (I): Formula (I).
8. The use according to any one of claims 1-6, wherein the medicament is adapted for oral administration; and/or, the effective dose of the asparagine endopeptidase inhibitor is 7.5 mg/kg.
9. A medicament for improving insulin resistance, comprising an asparagine endopeptidase inhibitor.
10. The medicament according to claim 9, further comprising pharmaceutically acceptable excipients; and/or, the structural formula of the asparagine endopeptidase inhibitor is shown as the following formula (I): Formula (I).

Description

Application of asparaginyl endopeptidase inhibitor in preparation of medicine for improving insulin resistance Technical Field The invention relates to the technical field of medicines, in particular to application of an asparagine endopeptidase inhibitor in preparing medicines for improving insulin resistance. Background Insulin resistance refers to a pathological condition in which the sensitivity of the target tissues (mainly skeletal muscle, liver and white adipose tissue) to insulin is reduced, i.e., normal levels of insulin cannot effectively promote glucose uptake by peripheral tissues, inhibit liver gluconeogenesis and regulate lipid metabolism, and the body needs to compensatory secrete a supraphysiological dose of insulin to maintain blood glucose homeostasis. However, current pharmaceutical intervention strategies for insulin resistance mostly target specific downstream effector molecules, metformin activating AMP-activated protein kinase (AMP-ACTIVATED PROTEIN KINASE, AMPK), thiazolidinediones (Thiazolidinediones, TZDs) activating peroxisome proliferator-activated receptors γ (Peroxisome proliferator-ACTIVATED RECEPTOR γ, pparγ). Although these drugs improve insulin sensitivity to some extent, they fail to intervene from an upstream source and have obvious side effects that thiazolidinediones can lead to weight gain and increased risk of fracture, and metformin, while being safer, has gastrointestinal side effects that limit long-term use in some patients. Thus, there is a great clinical need for new intervention strategies capable of targeting upstream driving factors, radically systematically improving insulin resistance. Disclosure of Invention It was found that aging itself is an independent risk factor for insulin resistance. Synergism of multiple senescence markers, such as mitochondrial dysfunction, chronic low-grade inflammation, reduced NAD + levels, and loss of autophagy, together drive age-related reduced insulin sensitivity. While asparaginyl endopeptidase (ASPARAGINE ENDOPEPTIDASE, AEP) is a lysosomal-localized cysteine protease, which has been shown to be a key molecule driving the pathological aging process, as a protease cleaving a variety of substrates, useful in neurodegenerative diseases. The application starts from inhibiting the aging driving factor AEP, and the AEP inhibitor is applied to the study of insulin resistance for the first time, and the AEP inhibitor is found to be capable of remarkably improving glucose tolerance and insulin sensitivity. Based on this, the present application provides the use of an asparagine endopeptidase inhibitor for the preparation of a medicament for improving insulin resistance. In a first aspect of the application there is provided the use of an asparagine endopeptidase inhibitor in the manufacture of a medicament for improving insulin resistance. The test proves that the AEP inhibitor not only remarkably enhances insulin sensitivity of old mice and improves glucose tolerance, but also reduces serum low density lipoprotein cholesterol and lactate dehydrogenase level, shows multiple improving effects on glucose metabolism and lipid metabolism, and has no obvious toxic or side effect in blood convention, urine convention and important organ pathology examination of heart, liver, spleen, lung, kidney and the like after long-term administration, thus proving that the AEP inhibitor has good safety and is suitable for long-term intervention of chronic diseases. In some embodiments, the asparagine endopeptidase inhibitor has the structural formula (I): Formula (I). In a second aspect, the application provides the use of an asparagine endopeptidase inhibitor for the preparation of a medicament for enhancing insulin sensitivity and/or modulating glucose tolerance. In some embodiments, the medicament is further capable of reducing the level of at least one of low density lipoprotein, cholesterol, and lactate dehydrogenase in serum. In a third aspect, the present application provides the use of an asparagine endopeptidase inhibitor in the manufacture of a medicament for the prevention or treatment of metabolic diseases. In some embodiments, the metabolic disease is an age-related metabolic disease; further, the metabolic disease includes insulin resistance caused by natural aging. In some embodiments, the asparagine endopeptidase inhibitor has the structural formula (I): Formula (I). In some embodiments, the medicament is suitable for oral administration; and/or, the effective dose of the asparagine endopeptidase inhibitor is 7.5 mg/kg. In a fourth aspect of the present application, there is provided a medicament for improving insulin resistance comprising an asparagine endopeptidase inhibitor. In some embodiments, a pharmaceutically acceptable adjuvant is also included; and/or, the structural formula of the asparagine endopeptidase inhibitor is shown as the following formula (I): Formula (I). Drawings FIG. 1 shows the results of the glucose toleran