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Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-13 , DOI: 10.1021/acs.jmedchem.4c01402 Joseph E Pero 1 , Elizabeth A Mueller 2 , Ashley M Adams 1 , Ramona S Adolph 3 , Parikshit Bagchi 2 , Dale Balce 2 , Marcus Bantscheff 3 , Ona Barauskas 2 , Istvan Bartha 2 , Dana Bohan 2 , Haiying Cai 2 , Esteban Carabajal 2 , James Cassidy 2 , Matthew Cato 1 , Khuram W Chaudhary 1 , Dingjun Chen 2 , Yi-Pei Chen 2 , Christophe Colas 2 , Isra Darwech 2 , H Christian Eberl 3 , Beth Fernandez 2 , Earl Gordon 1 , Johannes Grosse 2 , Justin Hansen 2 , Belinda Hetzler 2 , Seungmin Hwang 2 , Sam Jeyasingh 2 , Beatriz Kowalski 2 , Stephanie Lehmann 3 , Gary Lo 2 , Michael McAllaster 2 , Charles McHugh 1 , Corey Momont 2 , Zachary Newby 2 , Maria Nigro 2 , Fatai Oladunni 2 , Malar Pannirselvam 1 , Arnold Park 2 , Neil Pearson 1 , Andrew J Peat 1 , Bob Plastridge 2 , Rohit Ranjan 2 , Pegah Safabakhsh 2 , Nathan D Shapiro 2 , Leah Soriaga 2 , Neil Stokes 1 , David Sweeney 2 , Lindsey Talecki 1 , Amalio Telenti 2 , Ashley Terrell 2 , Winston Tse 2 , Lisha Wang 2 , Shuya Wang 1 , Laura Wedel 2 , Thilo Werner 3 , Deidre Dalmas Wilk 1 , Samantha Yim 2 , Jiayi Zhou 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-13 , DOI: 10.1021/acs.jmedchem.4c01402 Joseph E Pero 1 , Elizabeth A Mueller 2 , Ashley M Adams 1 , Ramona S Adolph 3 , Parikshit Bagchi 2 , Dale Balce 2 , Marcus Bantscheff 3 , Ona Barauskas 2 , Istvan Bartha 2 , Dana Bohan 2 , Haiying Cai 2 , Esteban Carabajal 2 , James Cassidy 2 , Matthew Cato 1 , Khuram W Chaudhary 1 , Dingjun Chen 2 , Yi-Pei Chen 2 , Christophe Colas 2 , Isra Darwech 2 , H Christian Eberl 3 , Beth Fernandez 2 , Earl Gordon 1 , Johannes Grosse 2 , Justin Hansen 2 , Belinda Hetzler 2 , Seungmin Hwang 2 , Sam Jeyasingh 2 , Beatriz Kowalski 2 , Stephanie Lehmann 3 , Gary Lo 2 , Michael McAllaster 2 , Charles McHugh 1 , Corey Momont 2 , Zachary Newby 2 , Maria Nigro 2 , Fatai Oladunni 2 , Malar Pannirselvam 1 , Arnold Park 2 , Neil Pearson 1 , Andrew J Peat 1 , Bob Plastridge 2 , Rohit Ranjan 2 , Pegah Safabakhsh 2 , Nathan D Shapiro 2 , Leah Soriaga 2 , Neil Stokes 1 , David Sweeney 2 , Lindsey Talecki 1 , Amalio Telenti 2 , Ashley Terrell 2 , Winston Tse 2 , Lisha Wang 2 , Shuya Wang 1 , Laura Wedel 2 , Thilo Werner 3 , Deidre Dalmas Wilk 1 , Samantha Yim 2 , Jiayi Zhou 2
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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.
中文翻译：
有效的 STT3A/B 抑制剂的发现及其多病原体抗病毒潜力和安全性评估
在 COVID-19 大流行之后，需要仔细考虑调节病毒生命周期常见生物途径的机会。人类中的N连接糖基化仅由寡糖转移酶复合物介导，并且经常被病毒劫持以促进感染。因此，OST 复合物的催化结构域 STT3A/B 成为具有广谱抗病毒潜力的有趣药物靶点。然而，由于N连接糖基化在许多基本人类过程中发挥着关键作用，STT3A/B 抑制的毒理学后果需要与抗病毒功效相称的关注。在此，我们描述了已知的 STT3A/B 抑制剂 NGI-1 如何启发人们发现卓越的工具化合物，并在体外功效和转化安全性（例如中枢神经系统、心血管、肝脏）研究中对其进行了评估。所描述的知识将吸引那些对调节N连接糖基化的治疗用途感兴趣的人以及更广泛的科学界。
更新日期：2024-08-13
中文翻译：
有效的 STT3A/B 抑制剂的发现及其多病原体抗病毒潜力和安全性评估
在 COVID-19 大流行之后，需要仔细考虑调节病毒生命周期常见生物途径的机会。人类中的N连接糖基化仅由寡糖转移酶复合物介导，并且经常被病毒劫持以促进感染。因此，OST 复合物的催化结构域 STT3A/B 成为具有广谱抗病毒潜力的有趣药物靶点。然而，由于N连接糖基化在许多基本人类过程中发挥着关键作用，STT3A/B 抑制的毒理学后果需要与抗病毒功效相称的关注。在此，我们描述了已知的 STT3A/B 抑制剂 NGI-1 如何启发人们发现卓越的工具化合物，并在体外功效和转化安全性（例如中枢神经系统、心血管、肝脏）研究中对其进行了评估。所描述的知识将吸引那些对调节N连接糖基化的治疗用途感兴趣的人以及更广泛的科学界。
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