作者: Safabakhsh, Pegah ; Bartha, Istvan ; Plastridge, Bob ; Wang, Lisha ; Bagchi, Parikshit ; Gordon, Earl ; McAllaster, Michael ; Momont, Corey ; Cato, Matthew ; Eberl, H. Christian ; Fernandez, Beth ; Newby, Zachary ; Kowalski, Beatriz ; Lehmann, Stephanie ; Cai, Haiying ; Nigro, Maria ; Yim, Samantha ; Park, Arnold ; Bohan, Dana ; Colas, Christophe ; Sweeney, David ; Chaudhary, Khuram W. ; Ranjan, Rohit ; Chen, Dingjun ; Peat, Andrew J. ; Darwech, Isra ; Pearson, Neil ; Barauskas, Ona ; Wedel, Laura ; Stokes, Neil ; Zhou, Jiayi ; Terrell, Ashley ; Pannirselvam, Malar ; Cassidy, James ; Telenti, Amalio ; Hetzler, Belinda ; Soriaga, Leah ; Talecki, Lindsey ; Oladunni, Fatai ; Hansen, Justin ; Mueller, Elizabeth A. ; Jeyasingh, Sam ; Bantscheff, Marcus ; Werner, Thilo ; Wang, Shuya ; Dalmas Wilk, Deidre ; Lo, Gary ; Shapiro, Nathan D. ; Balce, Dale ; Hwang, Seungmin ; Adams, Ashley M. ; Tse, Winston ; Carabajal, Esteban ; Grosse, Johannes ; Adolph, Ramona S. ; McHugh, Charles ; Chen, Yi-Pei ; Pero, Joseph E.

In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. N-linked glycosylation in humans is mediated exclusively by the oligosaccharyltransferase complex and is frequently hijacked by viruses to facilitate infection. As such, STT3A/B, the catalytic domain of the OST complex, became an intriguing drug target with broad-spectrum antiviral potential. However, due to the critical role N-linked glycosylation plays in a number of fundamental human processes, the toxicological ramifications of STT3A/B inhibition required attention commensurate to that given to antiviral efficacy. Herein, we describe how known STT3A/B inhibitor NGI-1 inspired the discovery of superior tool compounds which were evaluated in in vitro efficacy and translational safety (e.g., CNS, cardiovascular, liver) studies. The described learnings will appeal to those interested in the therapeutic utility of modulating N-linked glycosylation as well as the broader scientific community.

2020-01-01·British journal of pharmacology2区 · 医学

Delayed intervention with a novel SGLT2 inhibitor NGI001 suppresses diet‐induced metabolic dysfunction and non‐alcoholic fatty liver disease in mice

2区 · 医学

Article

作者: Chiang, Hao ; Huang, Hsing ; Lee, Jinq‐Chyi ; Liu, Hui‐Kang ; Huang, Cheng ; Huang, Hsiu‐Chen

Background and Purpose:

Non‐alcoholic fatty liver disease (NAFLD), including non‐alcoholic steatohepatitis, is closely related to metabolic diseases such as obesity and diabetes. Despite an accumulating number of studies, no pharmacotherapy that targets NAFLD has received general approval for clinical use.

Experimental Approach:

Inhibition of the sodium‐glucose cotransporter 2 (SGLT2) is a promising approach to treat diabetes, obesity, and associated metabolic disorders. In this study, we investigated the effect of a novel SGLT2 inhibitor, NGI001, on NAFLD and obesity‐associated metabolic symptoms in high‐fat diet (HFD)‐induced obese mice.

Key Results:

Delayed intervention with NGI001 protected against body weight gain, hyperglycaemia, hyperlipidaemia, and hyperinsulinaemia, compared with HFD alone. Adipocyte hypertrophy was prevented by administering NGI001. NGI001 inhibited impaired glucose metabolism and regulated the secretion of adipokines associated with insulin resistance. In addition, NGI001 supplementation suppressed hepatic lipid accumulation and inflammation but had little effect on kidney function. In‐depth investigations showed that NGI001 ameliorated fat deposition and increased AMPK phosphorylation, resulting in phosphorylation of its major downstream target, acetyl‐CoA carboxylase, in human hepatocyte HuS‐E/2 cells. This cascade ultimately led to the down‐regulation of downstream fatty acid synthesis‐related molecules and the up‐regulation of downstream β oxidation‐associated molecules. Surprisingly, NGI001 decreased gene and protein expression of SGLT1 and SGLT2 and glucose uptake in oleic acid‐treated HuS‐E/2 cells.

Conclusion and Implications:

Our findings suggest the novel SGLT2 inhibitor, NGI001 has therapeutic potential to attenuate or delay the onset of diet‐induced metabolic diseases and NAFLD.

2019-01-15·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

No Sugar Added: A New Strategy to Inhibit Glioblastoma Receptor Tyrosine Kinases

1区 · 医学

Article

作者: Lawrence, Theodore S. ; Wahl, Daniel R.

Abstract:

A novel inhibitor of N-linked glycosylation (NGI-1) inhibits the glycosylation and phosphorylation of multiple receptor tyrosine kinases in glioblastoma (GBM). NGI-1 sensitizes multiple models of GBM to chemotherapy and radiation in vitro and in vivo and may be especially effective in GBMs that retain active PTEN.See related article by Baro et al., p. 784

100 项与 NGI001 相关的药物交易

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