2. Academic Validation
  3. Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19

Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19

  • Sci Rep. 2021 Jun 24;11(1):13208. doi: 10.1038/s41598-021-92416-4.
Martin A Redhead 1,  C David Owen 2 3,  Lennart Brewitz 4,  Amelia H Collette 5,  Petra Lukacik 2 3,  Claire Strain-Damerell 2 3,  Sean W Robinson 5,  Patrick M Collins 5,  Philipp Schäfer 5,  Mark Swindells 5,  Chris J Radoux 5,  Iva Navratilova Hopkins 5,  Daren Fearon 2 3,  Alice Douangamath 2 3,  Frank von Delft 2 3 6 7,  Tika R Malla 4,  Laura Vangeel 8,  Thomas Vercruysse 8,  Jan Thibaut 8,  Pieter Leyssen 8,  Tu-Trinh Nguyen 9,  Mitchell Hull 9,  Anthony Tumber 5,  David J Hallett 5,  Christopher J Schofield 4,  David I Stuart 2 3 10 11,  Andrew L Hopkins 5,  Martin A Walsh 12 13
Affiliations

Affiliations

  • 1 Exscientia, The Schrödinger Building, Oxford Science Park, Oxford, OX4 4GE, UK. mredhead@exscientia.co.uk.
  • 2 Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
  • 3 Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, OX11 0FA, UK.
  • 4 Department of Chemistry, Chemistry Research Laboratory,, The Ineos Oxford Institute for Antimicrobial Research, 12 Mansfield Road, Oxford, OX1 3TA, UK.
  • 5 Exscientia, The Schrödinger Building, Oxford Science Park, Oxford, OX4 4GE, UK.
  • 6 Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK.
  • 7 Department of Biochemistry, University of Johannesburg, Auckland Park, 2006, South Africa.
  • 8 KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, 3000, Leuven, Belgium.
  • 9 Calibr, Scripps Research, 11119 N Torrey Pines Road, La Jolla, CA, 92037, USA.
  • 10 Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
  • 11 Instruct-ERIC, Oxford House, Parkway Court, John Smith Drive, Oxford, OX4 2JY, UK.
  • 12 Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK. martin.walsh@diamond.ac.uk.
  • 13 Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, OX11 0FA, UK. martin.walsh@diamond.ac.uk.
PMID: 34168183 DOI: 10.1038/s41598-021-92416-4
Abstract

Effective agents to treat coronavirus Infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main Protease (Mpro) and the papain-like Protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the Caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The Caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.

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