Health

Antiviral combination with therapeutic potential for COVID-19


Their findings at both the molecular and cellular levels demonstrate the enormous potential of new antiviral drug combinations to halt the spread of COVID-19 and other coronavirus diseases. Research published by

an open access journal from Nature Portfolio.

COVID has created an unprecedented public health crisis, with severe effects on the global economy and infrastructure; however, we can use the power of science to stop this pandemic“, said Columbia team leader Jingyue Ju, Samuel Ruben-Peter G. Viele Professor of Engineering; professor of chemical engineering and pharmacology; and director, Center for Gene Technology & Biomolecular Engineering .

We expect drug combinations like those we found to strongly inhibit RNA viruses such as SARS-CoV-2 and other coronaviruses that could lead to future pandemics. Because polymerases and exonucleases are highly conserved enzymes in coronaviruses with very rare mutations occurring in variants, we anticipate that therapeutics developed to target these enzymes should be used. universal for all coronaviruses with the potential to cause serious illness“.

SARS-CoV-2, the coronavirus that causes the global COVID-19 pandemic, uses a protein called polymerase to copy its RNA genome inside infected cells.

In theory, termination of the polymerase reaction should halt the spread of the coronavirus, leading to its destruction by the human host’s immune system. However, SARS-CoV-2 has two important enzymes that allow it to replicate: a polymerase that regenerates its RNA and a proofreading exonuclease to correct errors during replication.

The presence of proofreading exonucleases is unique to coronaviruses and is required to reduce the number of mutations and thus maintain the integrity and function of the large RNA genome of the coronavirus.

Thus, the vaccine approach has been quite effective in stopping the COVID-19 pandemic because coronaviruses do not mutate as frequently as influenza and HIV viruses, have no effector readout, and thus mutate. more often.

Nucleotide-based viral polymerase inhibitors are very successful drugs for the treatment of HIV infection and hepatitis B and C viruses.

However, because of the presence of proofreading exonucleases in SARS-CoV-2, which can remove these inhibitors from RNA, the polymerase inhibitor Remdesivir, the only FDA-approved drug for COVID-19, not as effective as expected in preventing critical illness.

If exonuclease can be simultaneously inhibited or its activity dodged, viral replication will be more effectively prevented.

The team, led by Ju and Dr. Thiago Souza, Full Research Fellow at the Oswaldo Cruz Institute’s Center for Health Technology Development, decided to investigate whether a combination of polymerase inhibitors and exonucleases may work together to inhibit replication of SARS-CoV-2 more or less effectively, or if polymerase inhibitors with certain modifications may resist removal by exonucleases.

The Columbia Engineering Group conceived of the overall project and carried out molecular studies to determine interactions between inhibitors and enzymes, using a novel mass spectrometry-based method. The Brazilian team designed and conducted cell studies to measure the inhibitory effects of the drug combination on virus reproduction.

Dr. Thomas Tuschl’s team at Rockefeller University and Dr. Dinshaw Patel’s team at Memorial Sloan Kettering Cancer Center have created polymerase and exonuclease complexes that are used in molecular studies.

Souza’s group demonstrated that the polymerase and exonuclease inhibitors work together to block the virus’s ability to reproduce in infected lung cells.

While these results were obtained in a cell culture model, we have intentionally chosen inhibitors that have been approved as drugs for the treatment of other common viral infections, such as viral diseases. HIV and hepatitis induced, with the aim of being able to quickly get them to clinical trials“, Souza noted.

Source: Medindia



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