Analysis of Thousands of Drugs Reveals Potential New COVID-19 Antivirals

Researchers from the Francis Crick Institute and the 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.

As COVID-19 vaccines roll out, there are still few drug options that can be used to treat patients with the virus, reduce symptoms and speed 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 (July 2, 2021) in the Biochemical Journal, the scientists identified 15 molecules that inhibit the growth of SARS-CoV-2 by blocking several enzymes involved in its replication.

The researchers developed and conducted tests on about 5,000 molecules provided by the Crick’s High Throughput Screening team to see if any of them effectively blocked the action of one of the seven SARS-CoV-2 enzymes. The tests were based on fluorescent changes with a special imaging instrument that detected whether enzymes were compromised.

They then validated and tested the potential inhibitors against SARS-CoV-2 in the lab to determine whether 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 mania and schizophrenia. Since there is existing safety data on these drugs, it may be possible to accelerate their development 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 have developed a chemical toolbox containing information on potential new COVID-19 drugs. We hope this will attract the attention of scientists with the drug development and clinical expertise needed to further test it, and ultimately see if a safe and effective treatment can be found for COVID-19 patients.”

The 15 molecules were also tested in combination with remdesivir, an antiviral drug used to treat patients with COVID-19. Four of these, all targeting the SARS-CoV-2 enzyme Nsp14 mRNA Cap methyltransferase, were shown to improve the effectiveness of this antiviral agent in lab tests.

The scientists now plan to conduct tests to see if a pairing of the 15 molecules they identified reduces the growth of the virus more than using them alone. Targeting enzymes involved in virus replication may also help prepare for future viral pandemics.

“Proteins on the outside of viruses evolve quickly, but within different classes of viruses are well-preserved proteins that change very little over time,” John added.

“If we can develop drugs that inhibit these proteins, they could provide a valuable first line of defense in the event of a future pandemic, before vaccines become available.”

References:

“Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of the nsp14 RNA Cap Methyltransferase” by Basu, S. et al., July 2, 2021, Biochemical Journal.
DOI: 10.1042/BCJ20210219

“Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of nsp5 Main Protease” by Milligan, J. et al., July 2, 2021, Biochemical Journal.
DOI: 10.1042/BCJ20210197

“Identification of SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp12/7/8 RNA-dependent RNA polymerase” by Bertolin, A. et al., July 2, 2021, Biochemical Journal.
DOI: 10.1042/BCJ20210200

“Identification of SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp13 helicase” by Zeng, J. et al., July 2, 2021, Biochemical Journal.
DOI: 10.1042/BCJ20210201

“Identification of SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3-papain-like protease” by Lim, CT. et al., July 2, 2021, Biochemical Journal.
DOI: 10.1042/BCJ20210244

“Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp15 Endoribonuclease” by Canal, B. et al., July 2, 2021, Biochemical Journal.
DOI: 10.1042/BCJ20210199

“Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease” by Canal, B. et al., July 2, 2021, Biochemical Journal.
DOI: 10.1042/BCJ20210198

The Francis Crick Institute is a biomedical research institute dedicated to understanding the fundamental biology underlying health and disease. Her work helps to understand why diseases develop and to translate discoveries into new ways to prevent, diagnose and treat diseases such as cancer, heart disease, stroke, infections and neurodegenerative diseases.

An independent organisation, the founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London.

Founded in 2015, The Crick moved in 2016 to a brand new, state-of-the-art building in central London, where 1500 scientists and support staff work together across disciplines, making it the largest single-roof biomedical research facility in Europe.