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Chemical inhibitors can reduce the ability of SARS-CoV-2 to infect host cell lines

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James McKerrow, MD, PhD, Dean of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, is a chronic parasite that primarily affects neglected tropical diseases, the poor and poorly serviced communities of developing countries. I have been studying infectious diseases for a long time. They are called “ignored” because there are few financial incentives for pharmaceutical companies to develop their treatments.

One of these neglected diseases is Chagas disease, a major cause of heart failure in Latin America, which is prevalent by the parasite-carrying “triatoma rubrofa”. Cruise Trypanosoma.. These parasites produce an enzyme called cruzine, which helps replicate and avoid the human immune system. McKelow’s research team is looking for inhibitors of cruzain, a small molecule that may form the basis of new antiparasitic drugs. One of the most effective cruzain inhibitors is called K777.

Then, in the spring of 2020, the COVID-19 pandemic began to spread throughout the United States.Researchers have found that SARS-CoV-2, a coronavirus that causes COVID-19, is a human enzyme. Cathepsin L cleaves viral peplomer.

And it’s just a coincidence that cathepsin L looks and works like Kurzain.

In a study published on March 31, 2021 ACS Chemical Biology, McKerrow and team show that inhibition of cathepsin L at low concentrations of K777 may reduce the ability of SARS-CoV-2 to infect four host cell lines without harming cells. I am.

“K777 inhibits human enzymes, not the virus itself, so we hope the virus is unlikely to develop resistance to it,” said co-author of a study with Dr. Thomas Meek of the University of Texas A & M. One McKerrow says.

K777 was not equally effective in all cell lines. This is probably because not all cell lines produced the same amount of cathepsin L or the same amount of ACE2. It is a host cell receptor used to latch into cells after the viral peplomer has been cleaved by cathepsin L. Inhibitors were optimal for the prevention of SARS. -CoV-2 infection in cells that produced the most cathepsin L and ACE2.

The cell lines tested were derived from African green monkey kidney epithelium, human cervical epithelium, and two types of human lung epithelium. Although an important research tool, such cell lines are not always representative of patients. Because they are cancer cells, they are easy to grow and manipulate in the laboratory, but it can also differ from the average person’s healthy lung or cervical cells in their molecular characteristics. It means that.

I was surprised how effective K777 was in stopping virus infections in the lab. However, under normal circumstances, it is impractical and unlikely that we can transfer the compound to clinical trials so quickly. We are fortunate that the “Home Entrepreneurs” program here at UC San Diego has helped fill that gap. “

James McKerrow, MD, PhD, Dean, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego

Selva Therapeutics, a privately held biotechnology company, is licensed for K777 from the University of California, San Diego. In parallel with this study, the company also fully tolerates therapies by those who participated in Phase I clinical trials to prevent lung injury and assess safety in the COVID-19 animal model. I found that. Selva is planning a phase IIa clinical trial in patients with COVID-19 who have not been hospitalized in late 2021.

Many people with COVID-19 experience mild illness and can recover at home with supportive care to help relieve their symptoms. Currently, severe cases of COVID-19 are treated with FDA-approved drugs such as the US Food and Drug Administration (FDA) antiviral drug remdesivir or monoclonals for use in hospitalized patients. There is a possibility. antibody. Worldwide, more than 124 million people have been diagnosed with COVID-19 and 2.72 million have died of infectious diseases.

Source:

Journal reference:

Melott, DM, et al. (2021) Clinical stage cysteine ​​protease inhibitors block SARS-CoV-2 infection in human and monkey cells. ACS Chemical Biology. doi.org/10.1021/acschembio.0c00875..

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