作者: Takebe, Takanori ; Watanabe-Chailland, Miki ; Dunn, Andrew ; Iwasawa, Kentaro ; Kumbaji, Meenasri ; Chaturvedi, Praneet ; Chung, Chuhan ; Myers, Robert P ; Zorn, Aaron M ; Gindin, Yevgeniy ; Yoneyama, Yosuke ; Kodaka, Asuka ; Kimura, Masaki ; Subramanian, G Mani ; Zhu, Gaohui ; Hwa, Vivian ; Wintzinger, Michelle ; Quattrocelli, Mattia ; Iguchi, Takuma ; Fujimoto, Masanobu ; Thompson, Wendy L

Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.

2021-01-01·European Journal of Medicinal Chemistry1区 · 医学

Application of sulfoximines in medicinal chemistry from 2013 to 2020

1区 · 医学

Review

作者: Xing, Kun ; Zhao, Linxiang ; Tong, Tong ; Yu, Huan ; Zhang, Yu ; Liu, Dan ; Han, Yu ; Cao, Hongxue ; Zhang, Jian ; Shi, Yuntao

In recent years, interest in sulfoximine chemistry has been greatly increased. For example, at least three sulfoximine containing drugs BAY 1143572, BAY 1251152 and AZD6738 have entered the clinic. Despite the increasing interest in sulfoximines and their chemistry, the routine application of this structure in drug discovery is still hampered due to limited experience in physicochemical and in vitro parameters of sulfoximines. Therefore, we reviewed all relevant articles from 2013 to the present in terms of potency and pharmacokinetic properties in order to support the addition of the sulfoximine component to the toolbox of medicinal chemists.

2017-06-20·Biochemistry

Antidiabetic Disruptors of the Glucokinase−Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface

Article

作者: Miller, Brian G. ; Martinez, Juliana A. ; Zakarian, Armen ; Xiao, Qing

The glucokinase regulatory protein (GKRP) plays an essential role in glucose homeostasis by acting as a competitive inhibitor of glucokinase (GCK) and triggering its localization to the hepatocyte nucleus upon glucose deprivation. Metabolites such as fructose 6-phosphate and sorbitol 6-phosphate promote assembly of the GCK-GKRP complex, whereas fructose 1-phosphate and functionalized piperazines with potent in vivo antidiabetic activity disrupt the complex. Here, we establish the molecular basis by which these natural and synthetic ligands modulate the GCK-GKRP interaction. We demonstrate that a small-molecule disruptor of the protein-protein interaction utilizes a two-step conformational selection mechanism to associate with a rare GKRP conformation constituting 3% of the total population. Conformational heterogeneity of GKRP is localized to the N-terminus and deleting this region eliminates the ability of sorbitol 6-phosphate to promote the GCK-GKRP interaction. Stabilizing ligands favor an extended N-terminus, which sterically positions two arginine residues for optimal Coulombic interaction with a pair of carboxylate side chains from GCK. Conversely, disruptors promote a more compact N-terminus in which an interfacial arginine residue is stabilized in an unproductive orientation through a cation-π interaction with tyrosine 75. Eliminating the ability to sample this binding impaired conformation enhances the intrinsic inhibitory activity of GKRP. Elucidating the molecular basis of ligand-mediated control over the GCK-GKRP interaction is expected to impact the development and future refinement of therapeutic agents for diabetes and cardiovascular disease, which result from improper GKRP regulation of GCK.

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