Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M<sup>pro</sup> from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants
The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M<sup>pro</sup>) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M<sup>pro</sup> inhibitor was the first such approved therapy. Although M<sup>pro</sup> inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify the noncovalent M<sup>pro</sup> inhibitor <b>5</b>, which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone <b>12</b> with significantly improved antiviral activity. Further optimization led to the potent lactam <b>26</b>, which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses.
Authors
- Anthony D. Keefe (ORCID: https://orcid.org/0000-0003-4548-2835)
- Matthew A. Clark
- Michael J. Sofia (ORCID: https://orcid.org/0000-0001-5574-9834)
- Débora L. Makino
- Andreas Schmitt
- John P. Guilinger
- Xiaohe Wang (ORCID: https://orcid.org/0000-0001-9650-5721)
- Stéphane Turcotte (ORCID: https://orcid.org/0000-0001-6031-4958)
- Angela M. Lam (ORCID: https://orcid.org/0000-0003-1050-0001)
- Shawn Johnstone
- Kayleigh R. McGovern-Gooch
- Philip A. Carpino (ORCID: https://orcid.org/0000-0002-7399-0717)
- Xu Wang (ORCID: https://orcid.org/0000-0001-7379-5789)
- Nagraj Mani (ORCID: https://orcid.org/0000-0002-8446-2338)
- Marvin M. Vega (ORCID: https://orcid.org/0000-0002-1034-0856)
- Franziska Preuß (ORCID: https://orcid.org/0000-0003-1616-4811)
- Chia-yi Chen
- Kristi Fan (ORCID: https://orcid.org/0000-0001-7100-4170)
- Breanna Tercero (ORCID: https://orcid.org/0000-0002-6184-9708)
- Archna Prasad
- Dimitar Gotchev (ORCID: https://orcid.org/0000-0001-7491-0179)
- K. Maskos
- Andrew G. Cole (ORCID: https://orcid.org/0000-0001-6707-2752)
- Jenny Liu (ORCID: https://orcid.org/0000-0002-3840-1438)
- Paolo A. Centrella
- Andrea Cuconati (ORCID: https://orcid.org/0000-0001-5123-0381)
- Ying Zhang (ORCID: https://orcid.org/0000-0002-8526-9636)
- Konstanze von König
Institutions
- Xenon Pharmaceuticals (Canada) (CA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02009
- Citations
- 4
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.56