Targeting the inter-monomeric space of TNFR1 pre-ligand dimers: A novel binding pocket for allosteric modulators DOI Creative Commons
Chih Hung Lo

Computational and Structural Biotechnology Journal, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a central role in signal transduction mediating inflammation and cell death associated with autoimmune neurodegenerative disorders. Inhibition of TNFR1 signaling is highly sought-after strategy to target these diseases. forms pre-ligand dimers held together by the assembly domain (PLAD), which essential for signaling. form crucial points interaction entire complex connecting TNF ligand bound trimeric receptors. While previous studies have shown feasibility disrupting dimeric interactions through competitive mechanism that targets PLAD, our recent demonstrated small molecules could also bind PLAD modulate an allosteric mechanism. Importantly, modulators alter dynamics propagate long-range conformational perturbation involves reshuffling receptors cytosolic domains without receptor-receptor or receptor-ligand interactions. In this study, we perform molecular docking previously reported on extracellular understand their binding sites interacting residues. We identify inter-monomeric space between as novel pocket modulators. further conduct pharmacological analyses bioactivity compounds residues properties. then provide insights into structure-activity relationship targeting dynamics. This paves way developing new therapeutic strategies designing chemical scaffolds

Язык: Английский

Exploring TNFR1: from discovery to targeted therapy development DOI Creative Commons
Yingying Li,

Ruiwei Ye,

Haorui Dai

и другие.

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 15, 2025

Язык: Английский

Процитировано

2
Therapeutic targeting of obesity-induced neuroinflammation and neurodegeneration DOI Creative Commons
Jialiu Zeng,

Lenny Yi Tong Cheong,

Chih Hung Lo

и другие.

Frontiers in Endocrinology, Год журнала: 2025, Номер 15

Опубликована: Янв. 17, 2025

Obesity is a major modifiable risk factor leading to neuroinflammation and neurodegeneration. Excessive fat storage in obesity promotes the progressive infiltration of immune cells into adipose tissue, resulting release pro-inflammatory factors such as cytokines adipokines. These inflammatory mediators circulate through bloodstream, propagating inflammation both periphery central nervous system. Gut dysbiosis, which results leaky intestinal barrier, exacerbates plays significant role linking pathogenesis neurodegeneration gut-brain/gut-brain-liver axis. Inflammatory states within brain can lead insulin resistance, mitochondrial dysfunction, autolysosomal increased oxidative stress. disruptions impair normal neuronal function subsequently cognitive decline motor deficits, similar pathologies observed neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease. Understanding underlying disease mechanisms crucial for developing therapeutic strategies address defects these metabolic pathways. In this review, we summarize provide insights different strategies, methods alter gut lifestyle changes, dietary supplementation, well pharmacological agents derived from natural sources, that target obesity-induced

Язык: Английский

Процитировано

2
Editorial: Lipid metabolism dysregulation in obesity-related diseases and neurodegeneration DOI Creative Commons
Jialiu Zeng, Chih Hung Lo

Frontiers in Endocrinology, Год журнала: 2025, Номер 16

Опубликована: Фев. 11, 2025

Editorial: Lipid Metabolism Dysregulation in Obesity-Related Diseases and Neurodegeneration Provisionally accepted

Язык: Английский

Процитировано

1
TNF receptors: Structure-function relationships and therapeutic targeting strategies DOI
Chih Hung Lo

Biochimica et Biophysica Acta (BBA) - Biomembranes, Год журнала: 2024, Номер unknown, С. 184394 - 184394

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

7
RANKL-derived peptide MHP1-AcN attenuates ovariectomy-induced osteoporosis by targeting RANK and TNFR1 in mice DOI Creative Commons
Takuya Kurihara, Munehisa Shimamura, Yuki Etani

и другие.

Bone, Год журнала: 2025, Номер 194, С. 117440 - 117440

Опубликована: Март 1, 2025

Estrogen deficiency following menopause increases receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteoblasts, thereby promoting osteoclast differentiation, and enhances T cell-derived tumor necrosis factor-alpha (TNFα) production, which induces sclerostin osteocytes, inhibiting bone formation. This study aimed to develop a novel uncoupling therapeutic agent for osteoporosis. We developed microglial healing peptide 1 with N-terminal acetylation C-terminal amidation (MHP1-AcN), modified RANKL lacking the activating CD loop. Given structural similarities RANK TNF (TNFR1), we hypothesized that MHP1-AcN could inhibit both RANKL-RANK TNFα-TNFR1 pathways address pathophysiology osteoporosis, as evaluated vitro vivo using an ovariectomized mouse model. In mice, inhibited osteoclastogenesis, reduced osteocytic expression, prevented loss, improved femoral cancellous cortical microarchitecture. Unlike anti-RANKL antibody, considerably preserved formation by osteoblasts enhanced strength, evidenced energy absorption capacity. vitro, bound TNFR1, suppressing activity via pathway reducing through TNFα-TNFR1-nuclear pathway. did not affect osteoblast proliferation differentiation or expression. effectively inhibits osteoclastogenesis sclerostin-mediated suppression while preserving function. These findings suggest MHP1-AcN, targets dual critical homeostasis, is promising

Язык: Английский

Процитировано

0
Targeting the inter-monomeric space of TNFR1 pre-ligand dimers: A novel binding pocket for allosteric modulators DOI Creative Commons
Chih Hung Lo

Computational and Structural Biotechnology Journal, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a central role in signal transduction mediating inflammation and cell death associated with autoimmune neurodegenerative disorders. Inhibition of TNFR1 signaling is highly sought-after strategy to target these diseases. forms pre-ligand dimers held together by the assembly domain (PLAD), which essential for signaling. form crucial points interaction entire complex connecting TNF ligand bound trimeric receptors. While previous studies have shown feasibility disrupting dimeric interactions through competitive mechanism that targets PLAD, our recent demonstrated small molecules could also bind PLAD modulate an allosteric mechanism. Importantly, modulators alter dynamics propagate long-range conformational perturbation involves reshuffling receptors cytosolic domains without receptor-receptor or receptor-ligand interactions. In this study, we perform molecular docking previously reported on extracellular understand their binding sites interacting residues. We identify inter-monomeric space between as novel pocket modulators. further conduct pharmacological analyses bioactivity compounds residues properties. then provide insights into structure-activity relationship targeting dynamics. This paves way developing new therapeutic strategies designing chemical scaffolds

Язык: Английский

Процитировано

0