1. Academic Validation
  2. Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety

Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety

  • J Med Chem. 2024 Aug 22;67(16):14586-14608. 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
Affiliations

Affiliations

  • 1 GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 2 Vir Biotechnology, Inc., 1800 Owens St., San Francisco, California 94158, United States.
  • 3 Cellzome GmbH, a GSK company, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Abstract

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.

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