Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes

Xu, Yixiang; Huang, Yunyuan; Song, Rui; Ren, Yanliang; Chen, Xin; Zhang, Chao; Mao, Fei; Li, Xiaokang; Zhu, Jin; Ni, Song; Wan, Jian; Li, Jian

doi:10.1016/j.ejmech.2020.112500

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…In addition, high expression of Gk can control blood glucose through accelerating insulin secretion and glycogen synthesis, which is beneficial for further reduced the blood glucose. FBPase is a key rate-limiting enzyme, which directly intervene glycogenolysis, glycolysis, and the tricarboxylic acid cycle ( Xu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Intestinal microbiomics and liver metabolomics insights into the preventive effects of chromium (III)-enriched yeast on hyperlipidemia and hyperglycemia induced by high-fat and high-fructose diet

Wang

Guo

Yang

et al. 2022

Current Research in Food Science

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Section: Discussionmentioning

confidence: 99%

Intestinal microbiomics and liver metabolomics insights into the preventive effects of chromium (III)-enriched yeast on hyperlipidemia and hyperglycemia induced by high-fat and high-fructose diet

Wang

Guo

Yang

et al. 2022

Current Research in Food Science

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“…Additionally, the intermediates generated from these metabolic cycles contribute to nucleotide synthesis, ribose generation, and the production of purine and pyrimidine nucleotides. 202 The strategic attenuation or abrogation of these substrate supplies by targeting key metabolic pathways could unlock novel therapeutic avenues in the battle against cancer. However, the realization of these promising therapies is contingent upon the development of highly specific and effective inhibitors.…”

Section: Targeting Nuclear Metabolic Products Via Inhibiting Metaboli...mentioning

confidence: 99%

Potential therapies targeting nuclear metabolic regulation in cancer

Chen,

Xu,

Liu

et al. 2023

MedComm

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The interplay between genetic alterations and metabolic dysregulation is increasingly recognized as a pivotal axis in cancer pathogenesis. Both elements are mutually reinforcing, thereby expediting the ontogeny and progression of malignant neoplasms. Intriguingly, recent findings have highlighted the translocation of metabolites and metabolic enzymes from the cytoplasm into the nuclear compartment, where they appear to be intimately associated with tumor cell proliferation. Despite these advancements, significant gaps persist in our understanding of their specific roles within the nuclear milieu, their modulatory effects on gene transcription and cellular proliferation, and the intricacies of their coordination with the genomic landscape. In this comprehensive review, we endeavor to elucidate the regulatory landscape of metabolic signaling within the nuclear domain, namely nuclear metabolic signaling involving metabolites and metabolic enzymes. We explore the roles and molecular mechanisms through which metabolic flux and enzymatic activity impact critical nuclear processes, including epigenetic modulation, DNA damage repair, and gene expression regulation. In conclusion, we underscore the paramount significance of nuclear metabolic signaling in cancer biology and enumerate potential therapeutic targets, associated pharmacological interventions, and implications for clinical applications. Importantly, these emergent findings not only augment our conceptual understanding of tumoral metabolism but also herald the potential for innovative therapeutic paradigms targeting the metabolism–genome transcriptional axis.

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“…To address this concern, we decided to discover a covalent binding site and novel covalent inhibitors of FBA from C. albicans (CaFBA) owing to the advantages of high potency, extended duration of action, and reduced risk for development of drug resistance to covalent inhibitors. − First, we determined the X-ray structure of CaFBA at 2.6 Å resolution, available in the Protein Data Bank (PDB ID: 6LNK). On the basis of the structural information of CaFBA, we found that CaFBA has an accessible noncatalytic cysteine within the reach of the substrate site, suggesting that there is a broad opportunity to discover covalent inhibitors for the treatment of azole-resistant IFIs.…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Discovery of the Novel Covalent Allosteric Site and Covalent Inhibitors of Fructose-1,6-Bisphosphate Aldolase to Overcome the Azole Resistance of Candidiasis

et al. 2022

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Fructose-1,6-bisphosphate aldolase (FBA) represents an attractive new antifungal target. Here, we employed a structure-based optimization strategy to discover a novel covalent binding site (C292 site) and the first-in-class covalent allosteric inhibitors of FBA from Candida albicans (CaFBA). Site-directed mutagenesis, liquid chromatography–mass spectrometry, and the crystallographic structures of APO–CaFBA, CaFBA–G3P, and C157S–2a4 revealed that S268 is an essential pharmacophore for the catalytic activity of CaFBA, and L288 is an allosteric regulation switch for CaFBA. Furthermore, most of the CaFBA covalent inhibitors exhibited good inhibitory activity against azole-resistant C. albicans, and compound 2a11 can inhibit the growth of azole-resistant strains 103 with the MIC80 of 1 μg/mL. Collectively, this work identifies a new covalent allosteric site of CaFBA and discovers the first generation of covalent inhibitors for fungal FBA with potent inhibitory activity against resistant fungi, establishing a structural foundation and providing a promising strategy for the design of potent antifungal drugs.

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Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes

Cited by 9 publications

References 51 publications

Intestinal microbiomics and liver metabolomics insights into the preventive effects of chromium (III)-enriched yeast on hyperlipidemia and hyperglycemia induced by high-fat and high-fructose diet

Intestinal microbiomics and liver metabolomics insights into the preventive effects of chromium (III)-enriched yeast on hyperlipidemia and hyperglycemia induced by high-fat and high-fructose diet

Potential therapies targeting nuclear metabolic regulation in cancer

Structure-Guided Discovery of the Novel Covalent Allosteric Site and Covalent Inhibitors of Fructose-1,6-Bisphosphate Aldolase to Overcome the Azole Resistance of Candidiasis

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