COVID-19 Therapeutic Potential Demonstrates by Antiviral Drug Combination

COVID-19 Therapeutic Potential Demonstrates by Antiviral Drug Combination ...

Researchers fromColumbia Engineering, theFiocruz Center for Health Technology and theOswaldo Cruz Institutein Brazil, the Memorial Sloan Kettering Cancer Center, and the Rockefeller University recently reported that by combining inhibitors of polymerases and exonucleases, they could reduce replication ten times more than when employing the polymerase inhibitors. They also identified a polymerase inhibitor with a unique mutation that often resists the spread of COVID-19 and other cor

COVID has created a massive public health crise, which has serious implications for the environment and infrastructure, but we can utilize science''s knowledge to resolve this epidemic, according to the Columbia team leaderJingyue Ju, Samuel Ruben-Peter G. Viele, a professor of chemical engineering and pharmacology, and director of the Center for Genome Technology and Biomolecular Engineering. We anticipate that therapeutics that were developed to target these enzymes should be widely applicable to all coronaviruses with

SARS-CoV-2, the global COVID-19 epidemic, uses a protein called polymerase to reintroduce its RNA genome inside infected human cells. In theory, terminating the polymerase reaction should reduce the spread of the coronavirus, causing its eradication by the human hosts immune system. However, SARS-CoV-2 has two key enzymes that allow it to replicate: the polymerase, which reproduces its RNA, and a proofreading exonu

The presence of the exonuclease for proofreading is unique to the coronaviruses and is necessary to reduce the number of mutations and thus maintain the integrity and function of the large RNA genomes of coronaviruses. Therefore, the vaccination method has been quite effective in managing the COVID-19 epidemic because the coronaviruses do not mutate as often as the influenza virus and HIV, which have no proofreading capability and therefore mutate more often.

The Nucleotide-based viral polymerase inhibitors are extremely effective in treating HIV and hepatitis patients. However, the proofreading exonuclease in SARS-CoV-2, which can remove these inhibitors from the RNA, isn''t as effective as anticipated in preventing serious illness. If the exonuclease is simultaneously inhibited or its activity evaded, viral replication would be enhanced.

We believe that drugs such as those we discovered will aggressively inhibit RNA viruses like SARS-CoV-2 and other coronaviruses that might result in future pandemics. JINGYUE JU

SAMUEL RUBEN-PETER G. VIELE PROFESSOR OF ENGINEERING; PROFESSOR OF CHEMICAL ENGINEERING AND PHARMACOLOGY; AND DIRECTOR, CENTER FOR GENOME TECHNOLOGY & BIOMOLECULAR ENGINEERING

The Colombia Engineering team, led by Ju and Dr. Thiago Souza, the full researcher at the Oswaldo Cruz Institutes Center for Technological Development in Health, decided to investigate whether the combination of polymerase and exonuclease inhibitors might work together to prevent replication of SARS-CoV-2 more effectively, or if polymerase inhibitors with certain modifications might resist removal by the exonuclease. The Brazilian team, according to a recent mass-spectrometry study,

The polymerase and exonuclease inhibitors collaborate to ensure that viruses are capable of reproduce in infected lung cells. However, we purposely chose inhibitors that were previously approved as drugs for treatment of other common virus infections, such as those caused by HIV and hepatitis, with the aim of being able to speed them up to clinical trials.

The organization is now looking at whether combination medications may be used in a COVID-19 animal model, with appropriate pharmacological properties. These drugs can be shipped rapidly to clinical trials if the results are positive. The group has also established a partnership with a consortium of pharmacologists, virologists, medicinal chemists, and structural biologists to develop new therapeutics that can increase their potential and safety profiles for COVID-19.

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