James McKerrow, MD, Ph.D., dean of the Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego, has long studied neglected tropical diseases — chronic and disabling parasitic infections and parasitic heart disease that primarily affect poor and underserved communities in developing nations. One of these neglected diseases is Chagas disease, the leading cause of heart failure in Latin America, which is spread by “kissing bugs” carrying the parasite Trypanosoma cruzi. These parasites produce an enzyme called cruzain that helps them replicate and evade the human immune system. McKerrow’s research team looks for inhibitors of cruzain — small molecules that might form the basis for new anti-parasitic medicines. One particularly effective cruzain inhibitor is called K777.
The COVID-19 pandemic then began to spread across the United States in the spring of 2020. SARS-CoV-2, the coronavirus that causes COVID-19, can’t dock on and infect human cells unless a human enzyme called cathepsin L cleaves the virus’ spike protein, according to researchers. And it just so happens that cathepsin L resembles cruzain in appearance and function. McKerrow and his colleagues report in ACS Chemical Biology on March 31, 2021, those low concentrations of K777 inhibit cathepsin L, which reduces SARS-ability CoV-2’s to infect four host cell lines while causing no harm to the cells.
K777 wasn’t equally effective in all cell lines. The inhibitor was best at preventing SARS-CoV-2 infection in the 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. While an important research tool, cell lines such as these are not necessarily representative of patients. They are easy to grow and manipulate in research laboratories because they are cancer cells, but that also means their molecular features likely differ from the average person’s healthy lung or cervical cells.
“We were surprised at just how effective K777 is in blocking viral infection in the lab,” McKerrow said. “Yet under usual circumstances, it would be impractical and unlikely that we ourselves would be able to move the compound so quickly into clinical trials. We’re fortunate that an ‘entrepreneur-in-residence program here at UC San Diego has helped bridge that gap.”
Selva Therapeutics, a privately held biotechnology company, has licensed K777 from UC San Diego. In parallel with this study, the company has also found that the experimental therapy of parasitic heart disease prevented lung damage in COVID-19 animal models and was well-tolerated by people who participated in Phase I clinical trial to assess safety. Selva is planning a Phase II clinical trial in non-hospitalized COVID-19 patients for late 2021.
