2. Academic Validation
  3. Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 Mpro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants

Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 Mpro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants

  • J Med Chem. 2024 Nov 14;67(21):19623-19667. doi: 10.1021/acs.jmedchem.4c02009.
Xu Wang 1,  Dimitar Gotchev 1,  Kristi Yi Fan 1,  Marvin M Vega 1,  Nagraj Mani 1,  Kayleigh McGovern-Gooch 1,  Andrea Cuconati 1,  Breanna Tercero 1,  Xiaohe Wang 1,  Philip Carpino 2,  Klaus Maskos 3,  Paolo A Centrella 4,  Andreas Schmitt 3,  Franziska Preuss 3,  Archna Prasad 3,  Chia-Yi Chen 3,  Matthew A Clark 4,  John P Guilinger 4,  Shawn Johnstone 2,  Konstanze von König 3,  Anthony D Keefe 4,  Jenny Liu 4,  Stéphane Turcotte 2,  Ying Zhang 4,  Debora L Konz Makino 3,  Angela M Lam 1,  Andrew G Cole 1,  Michael J Sofia 1
Affiliations

Affiliations

  • 1 Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States.
  • 2 X-Chem Inc., 4800 Rue Levy Suite 200, Montreal, QC CA H4R 2P7, Canada.
  • 3 Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany.
  • 4 X-Chem Inc., 100 Beaver Street Suite 101, Waltham, Massachusetts 02453, United States.
PMID: 39453309 DOI: 10.1021/acs.jmedchem.4c02009
Abstract

The recent global COVID-19 pandemic has highlighted treatments for coronavirus Infection as an unmet medical need. The main protease (Mpro) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent Mpro inhibitor was the first such approved therapy. Although Mpro 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 Mpro inhibitor 5, which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone 12 with significantly improved Antiviral activity. Further optimization led to the potent lactam 26, which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from Other coronaviruses.

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