Study: Inhibiting of Enzymes in SARS-CoV-2 Reduces Replication by 10 Times

By combining inhibitors of polymerases and exonucleases, which are enzymes that allow SARS-CoV-2 to reproduce, investigators were able to reduce SARS-CoV-2 replication 10 times more than when they were using just the polymerase inhibitors.

The investigators also identified that a polymerase inhibitor with a unique modification largely resists its removal from the RNA by the exonuclease.

These findings, from both cellular and molecular levels, show the potential of novel antiviral drug combinations to stop the spread of COVID-19, as well as other coronavirus diseases.

“We expect drug combinations like the ones we found will powerfully inhibit RNA viruses such as SARS-CoV-2 and other coronaviruses that could lead to future pandemics,” Jingyue Ju, director of Center for Genome Technology & Biomolecular Engineering at Columbia University, said in a statement. “Because polymerase and exonuclease are highly conserved enzymes in coronaviruses with very rare mutations appearing in variants, we anticipate that therapeutics developed to target these enzymes should be widely applicable to all coronaviruses with the potential to cause serious disease.”.

The polymerase is used to replicate the SARS-CoV-2 RNA genome, so, in theory, destroying it should stop the replication of the coronavirus. The presence of exonuclease is essential for proofreading the coronaviruses and is needed to help reduce the number of mutations. It is used to maintain the function and integrity of the RNA genomes.

Together, the 2 enzymes allow the virus to replicate with the polymerase, allowing it to reproduce RNA and exonuclease, which corrects errors in the replication process.

Vaccines have been effective at containing COVID-19 infections because coronaviruses do not mutate as frequently as HIV or influenza, which do not have the “proofreading” function.

Because of the presence of exonuclease, the polymerase inhibitor, Remdesivir, which is the only FDA-approved medication to treat COVID-19, might not be as effective at preventing the disease as previously thought.

The exonuclease would need to be concurrently inhibited or its activation evaded for viral replication to be efficiently blocked.

Investigators looked at whether the combination of the enzyme inhibitors could work together to inhibit the replication more effectively or if polymerase inhibitors could be effective following the removal of the exonuclease.

The investigators from Columbia Engineering performed molecular-level studies to identify the different interactions and used a novel mass-spectrometry-based approach.

The team from Brazil designed and conducted cellular studies to measure the inhibitory effects of drug combinations on viral reproduction.

Meanwhile, the teams at Memorial Sloan Kettering Cancer Center and Rockefeller University produced the polymerase and exonuclease complexes used in the molecular studies.

The findings showed that the 2 inhibitors could work together to block the virus’ ability to reproduce in infected lung cells.

Investigators are exploring whether the enhanced antiviral effects of the combination drugs can be demonstrated in a COVID-19 animal model with acceptable pharmacological properties.

The results were published in Communications Biology, an open access journal from Nature Portfolio.

The investigators were from Columbia Engineering, the Oswaldo Cruz Foundation’s Center for Technological Development in Health, the Oswaldo Cruz Institute, Memorial Sloan Kettering Cancer Center, and Rockefeller University.

Reference

Novel antiviral drug combinations demonstrate COVID-19 therapeutic potential. EurekAlert. News release. March 7, 2022. Accessed March 23, 2022. https://www.eurekalert.org/news-releases/945586