2. Academic Validation
  3. Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity

Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity

  • J Med Chem. 2022 Feb 24;65(4):2940-2955. doi: 10.1021/acs.jmedchem.1c01307.
Zhengnan Shen 1 2 3,  Kiira Ratia 1 4,  Laura Cooper 1 5,  Deyu Kong 1 2,  Hyun Lee 1 4,  Youngjin Kwon 4,  Yangfeng Li 1 2,  Saad Alqarni 1,  Fei Huang 1 2,  Oleksii Dubrovskyi 1 2,  Lijun Rong 5,  Gregory R J Thatcher 3,  Rui Xiong 1 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States.
  • 2 UICentre (Drug Discovery at UIC), University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States.
  • 3 Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 4 Research Resources Center, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States.
  • 5 Department of Microbiology, College of Medicine, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States.
PMID: 34665619 DOI: 10.1021/acs.jmedchem.1c01307
Abstract

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar Antiviral potency in SARS-CoV-2-infected human cells.

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