Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety
In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. <i>N</i>-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 <i>N</i>-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 <i>in vitro</i> efficacy and translational safety (e.g., CNS, cardiovascular, liver) studies. The described learnings will appeal to those interested in the therapeutic utility of modulating <i>N</i>-linked glycosylation as well as the broader scientific community.
Authors
- Jiayi Zhou (ORCID: https://orcid.org/0000-0002-4231-3422)
- Malar Pannirselvam
- Joseph E. Pero (ORCID: https://orcid.org/0000-0003-2674-4713)
- Michael R. McAllaster (ORCID: https://orcid.org/0000-0001-9729-7290)
- Ona Barauskas (ORCID: https://orcid.org/0000-0001-9878-5763)
- Charles F. McHugh
- Ashley M. Adams (ORCID: https://orcid.org/0000-0003-0823-3709)
- Christophe Colas
- Johannes Grosse (ORCID: https://orcid.org/0000-0003-3288-0455)
- Deidre A. Dalmas (ORCID: https://orcid.org/0000-0003-3641-139X)
- Lindsey Talecki (ORCID: https://orcid.org/0000-0003-3516-717X)
- Andrew J. Peat (ORCID: https://orcid.org/0000-0003-4351-5541)
- Maria Concetta Nigro (ORCID: https://orcid.org/0000-0003-3834-6122)
- Beth Fernandez
- Elizabeth A. Mueller (ORCID: https://orcid.org/0000-0001-5482-6551)
- Earl Gordon
- Fatai S. Oladunni (ORCID: https://orcid.org/0000-0001-5050-0183)
- Haiying Cai (ORCID: https://orcid.org/0000-0002-8902-9269)
- Dale R. Balce (ORCID: https://orcid.org/0000-0001-5123-530X)
- Thilo Werner (ORCID: https://orcid.org/0000-0003-0688-5834)
- Laura Wedel
- Neil D. Pearson (ORCID: https://orcid.org/0000-0002-0026-9603)
- Ramona S. Adolph (ORCID: https://orcid.org/0000-0001-5143-5977)
- Belinda E. Hetzler (ORCID: https://orcid.org/0000-0002-0372-9126)
- H. Christian Eberl (ORCID: https://orcid.org/0000-0002-4159-5958)
- Rohit Ranjan
- Neil R. Stokes (ORCID: https://orcid.org/0000-0001-9984-6521)
- Matthew J. Cato
- Marcus Bantscheff (ORCID: https://orcid.org/0000-0002-8343-8977)
- Leah Soriaga (ORCID: https://orcid.org/0000-0001-5852-741X)
- Amalio Telenti (ORCID: https://orcid.org/0000-0001-6290-7677)
- Yi-Pei Chen
- István Bartha (ORCID: https://orcid.org/0000-0003-3360-1999)
- Dana Bohan (ORCID: https://orcid.org/0000-0002-9239-3053)
- Arnold Park (ORCID: https://orcid.org/0000-0001-8916-2230)
- Parikshit Bagchi (ORCID: https://orcid.org/0000-0002-8016-4966)
- Zachary E. Newby
- Seungmin Hwang (ORCID: https://orcid.org/0000-0003-0846-5462)
- Pegah Safabakhsh
- Winston C. Tse
- Samantha S. Yim (ORCID: https://orcid.org/0009-0007-8567-3501)
- Khuram W. Chaudhary (ORCID: https://orcid.org/0000-0001-5693-0491)
- David Sweeney
- Corey Momont
- Shuya Wang (ORCID: https://orcid.org/0000-0001-6650-5835)
- Lisha Wang (ORCID: https://orcid.org/0000-0002-6482-1073)
- Sam Jeyasingh
- Bob Plastridge
- Isra Darwech
- B. Kowalski
- Dingjun Chen
- James T. Cassidy
- Stephanie Lehmann
- J oslash rgen Fischer Hansen
- Esteban Carabajal
- G.F. Lo
- A. Terrell
- Nathan D. Shapiro
Institutions
- South College (US)
- VIR Biotechnology (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01402
- Citations
- 7
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- GlaxoSmithKline
- Vir Biotechnology