Article Metrics


Online attention

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

DOI: 10.1038/s41598-021-92416-4 DOI Help

Authors: Martin A. Redhead (Exscientia) , C. David Owen (Diamond Light Source; Research Complex at Harwell) , Lennart Brewitz (The Ineos Oxford Institute for Antimicrobial Research) , Amelia H. Collette (Exscientia) , Petra Lukacik (Diamond Light Source; Research Complex at Harwell) , Claire Strain-Damerell (Diamond Light Source; Research Complex at Harwell) , Sean W. Robinson (Exscientia) , Patrick M. Collins (Exscientia) , Philipp Schäfer (Exscientia) , Mark Swindells (Exscientia) , Chris J. Radoux (Exscientia) , Iva Navratilova Hopkins (Exscientia) , Daren Fearon (Diamond Light Source; Research Complex at Harwell) , Alice Douangamath (Diamond Light Source; Research Complex at Harwell) , Frank Von Delft (Diamond Light Source; Research Complex at Harwell; Structural Genomics Consortium, University of Oxford; University of Johannesburg) , Tika R. Malla (The Ineos Oxford Institute for Antimicrobial Research) , Laura Vangeel (Rega Institute) , Thomas Vercruysse (Rega Institute) , Jan Thibaut (Rega Institute) , Pieter Leyssen (Rega Institute) , Tu-Trinh Nguyen (Calibr, Scripps Research) , Mitchell Hull (Calibr, Scripps Research) , Anthony Tumber (Exscientia) , David J. Hallett (Exscientia) , Christopher J. Schofield (The Ineos Oxford Institute for Antimicrobial Research) , David I. Stuart (Diamond Light Source; Research Complex at Harwell; Wellcome Centre for Human Genetics, University of Oxford; Instruct-ERIC) , Andrew L. Hopkins (Exscientia) , Martin A. Walsh (Diamond Light Source)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Scientific Reports , VOL 11

State: Published (Approved)
Published: June 2021

Open Access Open Access

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.

Journal Keywords: Enzyme mechanisms; High-throughput screening; SARS-CoV-2; X-ray crystallography

Diamond Keywords: COVID-19; Viruses; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 28/06/2021 10:49


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)