Researchers at the Francis Crick Institute and University of Dundee have screened thousands of drug and chemical molecules and identified a range of potential antivirals that could be developed into new treatments for COVID-19 or in preparation for future coronavirus outbreaks.
While COVID-19 vaccines are being rolled out, there are still few drug options that can be used to treat patients with the virus, to reduce symptoms and speed up recovery time. These treatments are especially important for groups where the vaccines are less effective, such as some patients with blood cancers.
In a series of seven papers, published today (2 July) in the Biochemical Journal, the scientists identified 15 molecules which inhibit the growth of SARS-CoV-2 by blocking different enzymes involved in its replication.
The researchers developed and ran tests for around 5,000 molecules provided by the Crick's High Throughput Screening team to see if any of these effectively blocked the functioning of any of seven SARS-CoV-2 enzymes. The tests were based on fluorescent changes with a special imaging tool detecting if enzymes had been affected.
They then validated and tested the potential inhibitors against SARS-CoV-2 in the lab, to determine if they effectively slowed viral growth. The team found at least one inhibitor for all seven enzymes.
Three of the molecules identified are existing drugs, used to treat other diseases. Lomeguatrib is used in melanoma and has few side-effects, suramin is a treatment for African sleeping sickness and river blindness and trifluperidol is used in cases of mania and schizophrenia. As there is existing safety data on these drugs, it may be possible to more quickly develop these into SARS-CoV-2 antivirals.
John Diffley, lead author of the papers and associate research director and head of the Chromosome Replication Laboratory at the Crick, said: "We've developed a chemical toolbox of information about potential new COVID-19 drugs. We hope this attracts attention from scientists with the drug development and clinical expertise needed to test these further, and ultimately see if any could become safe and effective treatments for COVID-19 patients."
The 15 molecules were also tested in combination with remdesivir, an antiviral being used to treat patients with COVID-19. Four of these, all which target the SARS-CoV-2 enzyme Nsp14 mRNA Cap methyltransferase, were found to improve the effectiveness of this antiviral in lab tests.
The scientists now plan to run tests to see if any pairing of the 15 molecules they identified decrease the virus' growth more than if they are used alone. Targeting enzymes involved in virus replication could also help prepare for future viral pandemics.
"Proteins on the outside of viruses evolve rapidly but within different classes of viruses are well conserved proteins that change very little with time," adds John.
"If we can develop drugs that inhibit these proteins, in the situation of a future pandemic, they could provide a valuable first line of defence, before vaccines become available."
For further information, contact: email@example.com or +44 (0)20 3796 5252
Notes to Editors
Basu, S. et al. (2021). Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of the nsp14 RNA Cap Methyltransferase. Biochemical Journal. 10.1042/BCJ20210219
Milligan, J. et al. (2021). Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of nsp5 Main Protease. Biochemical Journal. 10.1042/BCJ20210197
Bertolin, A. et al. (2021). Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp12/7/8 RNA-dependent RNA Polymerase. Biochemical Journal. 10.1042/BCJ20210200
Zeng, J. et al. (2021). Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp13 Helicase. Biochemical Journal. 10.1042/BCJ20210201
Lim, CT. et al. (2021). Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp3 Papain-like Protease. Biochemical Journal. 10.1042/BCJ20210244
Canal, B. et al. (2021). Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp15 Endoribonuclease. Biochemical Journal. 10.1042/BCJ20210199
Canal, B. et al. (2021). Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease. Biochemical Journal. 10.1042/BCJ20210198
The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.
An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King's College London.
The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe.
Biochemical Journal. Celebrating 115 years since its first publication, the Biochemical Journal has been at the forefront of biomedical advancement for over a century. Continuing to break new ground in the fields of biochemistry, cellular biosciences, and molecular biology, rigorous understanding of molecular mechanisms in biology remains at the core of its mission. The journal is proud to play a key role in advancing understanding through publication of high-impact research from across the world, leading the way in an era of rapid change and contributing to 21st-century innovation in biochemistry.
Published by Portland Press, the Biochemical Society's wholly-owned publishing arm, the Biochemical Journal forms part of a portfolio of seven journals that return all profits to the life science community in support of the Society's charitable objectives.
Find out more at portlandpress.com/biochemj