更新于：2024-11-01

OGA x β-N-乙酰氨基己糖苷酶

更新于：2024-11-01

基本信息

关联

项与 OGA x β-N-乙酰氨基己糖苷酶相关的药物

LY-3372689

靶点

β-N-乙酰氨基己糖苷酶 x OGA

作用机制

β-N-乙酰氨基己糖苷酶抑制剂 [+2]

在研机构

Eli Lilly & Co.

原研机构

Eli Lilly & Co.

在研适应症

阿尔茨海默症

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 OGA x β-N-乙酰氨基己糖苷酶相关的临床试验

NCT05749848 / Completed临床1期

Open-Label Study to Assess the Disposition of [14C]-LY3372689 Following Oral Administration in Healthy Male Participants

The main purpose of this study is to evaluate how much of the study drug (LY3372689), administered as a single dose that has the radioactive substance 14C incorporated into it, passes from blood into urine, feces and expired air in healthy male participants. The study will also measure how much of the study drug gets into the bloodstream, how its broken down, and how long it takes the body to get rid of it. The study will last about 4 weeks. Screening is required within 28 days prior to the start of the study and follow up is required approximately 7 days after discharge.

开始日期2023-02-24

申办/合作机构

Eli Lilly & Co.

NCT05063539 / Active, not recruiting临床2期

Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early Symptomatic Alzheimer's Disease

The purpose of this study is to assess the safety, tolerability and effect of study drug LY3372689 in participants with early symptomatic Alzheimer's Disease

开始日期2021-09-16

申办/合作机构

Eli Lilly & Co.

NCT04392271 / Completed临床1期

Assessment of Brain O-GlcNAcase (OGA) Enzyme Occupancy After Multiple Oral Doses of LY3372689 as Measured by Positron Emission Tomography (PET) With the Radioligand [18F]LY3316612 in Healthy Subjects

This study uses imaging to evaluate how LY3372689 binds to a protein in the brain. This study will be conducted in healthy participants and will last up to about 10 weeks. Screening must be completed within four weeks prior to enrollment.

开始日期2020-08-06

申办/合作机构

Eli Lilly & Co.

100 项与 OGA x β-N-乙酰氨基己糖苷酶相关的临床结果

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100 项与 OGA x β-N-乙酰氨基己糖苷酶相关的转化医学

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0 项与 OGA x β-N-乙酰氨基己糖苷酶相关的专利（医药）

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项与 OGA x β-N-乙酰氨基己糖苷酶相关的文献（医药）

2019-10-28·Journal of Chemical Information and Modeling2区 · 化学

Discovery of Novel Inhibitors Targeting Human O-GlcNAcase: Docking-Based Virtual Screening, Biological Evaluation, Structural Modification, and Molecular Dynamics Simulation

2区 · 化学

Article

作者: Zhang, Jianjun ; Shen, Shengqiang ; Lu, Huizhe ; Dong, Lili ; Yang, Qing ; Chen, Wei ; Xu, Dongdong

β-N-Acetylhexosaminidases have emerged as promising targets for drug and pesticide discovery due to their critical physiological functions in various cellular processes. In particular, human O-GlcNAcase (hOGA) from the glycoside hydrolase family 84 (GH84) has gained significant attention. This enzyme was found to be linked to various diseases such as diabetes, cancer, and Alzheimer's disease (AD). In this study, to develop novel hOGA inhibitors with suitable pharmaceutical properties, virtual screening of the Drugbank database was performed using a docking-based approach targeting hOGA. Chlorhexidine (4, K_i = 4.0 μM) was identified as a potent hOGA inhibitor with excellent selectivity (K_i > 200 μM against human β-N-acetylhexosaminidase B) and subjected to structural modifications and SAR studies. Furthermore, molecular dynamics simulations as well as binding free energy and free energy decomposition calculations were carried out to investigate the basis for the efficiency of potent inhibitors against hOGA. This present work revealed the new application of the disinfectant chlorhexidine and provided useful information for the future design of hOGA inhibitors.

2018-10-01·Cell Chemical Biology1区 · 生物学

A Glycoengineered Enzyme with Multiple Mannose-6-Phosphates Is Internalized into Diseased Cells to Restore Its Activity in Lysosomes

1区 · 生物学

Article

作者: Hyun, Ji Young ; Kim, Sanggil ; Shin, Injae ; Lee, Hyun Soo

In this study we developed an efficient method to prepare glycoengineered β-N-acetylhexosaminidase containing multiple mannose-6-phosphates (M6Ps) by combining genetic code expansion with bioorthogonal ligation techniques. We found that multiple M6P-conjugated enzymes were produced with a high efficiency by using combined techniques. Importantly, glycoengineered enzymes entered lysosomes of patient-derived primary cells, which lack endogenous lysosomal β-N-acetylhexosaminidase, more readily than commercialized human β-hexosaminidase. Moreover, glycoengineered enzymes successfully removed GM2-ganglioside stored in lysosomes of diseased cells, indicating that its activity is restored in diseased cells. We also synthesized and applied a lysosome-targeting fluorogenic substrate to monitor endogenous and supplemental glycoengineered β-N-acetylhexosaminidase activities in lysosomes. The results of this study indicate that the present strategy, which relies on genetic code expansion and bioorthogonal ligation techniques, is highly attractive to generate multi-M6P-containing lysosomal enzymes that can be used to study lysosomal storage disorders associated with lysosomal enzyme deficiencies.

2014-02-01·Human Molecular Genetics2区 · 生物学

Reversibility of neuropathology in Tay–Sachs-related diseases

2区 · 生物学

Article

作者: Robin Ziegler ; Seng H. Cheng ; Susan Z. Wang ; Timothy M. Cox ; Marõ ´ a-Begona Cachon-Gonzalez

The GM2 gangliosidoses are progressive neurodegenerative disorders due to defects in the lysosomal β-N-acetylhexosaminidase system. Accumulation of β-hexosaminidases A and B substrates is presumed to cause this fatal condition. An authentic mouse model of Sandhoff disease (SD) with pathological characteristics resembling those noted in infantile GM2 gangliosidosis has been described. We have shown that expression of β-hexosaminidase by intracranial delivery of recombinant adeno-associated viral vectors to young adult SD mice can prevent many features of the disease and extends lifespan. To investigate the nature of the neurological injury in GM2 gangliosidosis and the extent of its reversibility, we have examined the evolution of disease in the SD mouse; we have moreover explored the effects of gene transfer delivered at key times during the course of the illness. Here we report greatly increased survival only when the therapeutic genes are expressed either before the disease is apparent or during its early manifestations. However, irrespective of when treatment was administered, widespread and abundant expression of β-hexosaminidase with consequent clearance of glycoconjugates, α-synuclein and ubiquitinated proteins, and abrogation of inflammatory responses and neuronal loss was observed. We also show that defects in myelination occur in early life and cannot be easily resolved when treatment is given to the adult brain. These results indicate that there is a limited temporal opportunity in which function and survival can be improved-but regardless of resolution of the cardinal pathological features of GM2 gangliosidosis, a point is reached when functional deterioration and death cannot be prevented.