Ayooshi Mitra, Amity University, Kolkata
UC San Diego researchers have long studied neglected tropical diseases, which are chronic and disabling parasitic infections that primarily affect underprivileged communities in developing countries. They are referred to as “neglected” because pharmaceutical companies have little financial incentive to develop therapies for them. Chagas disease, the leading cause of heart failure in Latin America, is one of these neglected diseases. It is spread by “kissing bugs” carrying the parasite Trypanosoma cruzi. Cruzain is an enzyme produced by these parasites that aids in their replication and evasion of the human immune system. The research group is looking for cruzain inhibitors, which are small molecules that could be used to develop new anti-parasitic drugs. K777 is a cruzain inhibitor that is particularly effective.
The COVID-19 pandemic then began to sweep through the United States in the spring of 2020. Because K777 inhibits a human enzyme rather than the virus itself, the researchers believe the virus will be less likely to develop resistance to it. K777 did not work equally well in all cell lines. This is most likely since not all cell lines produced the same amount of cathepsin L or ACE2, the host cell receptor that the virus’ spike protein uses to latch onto cells after being cleaved by cathepsin L. In cells that produced the most cathepsin L and ACE2, the inhibitor was most effective at preventing SARS-CoV-2 infection. The cell lines used in the study were derived from African green monkey kidney epithelial cells, human cervical epithelial cells, and two types of human lung epithelial cells. While useful for research, cell lines like these are not always representative of patients. Because they are cancer cells, they are easy to grow and manipulate in research laboratories; however, their molecular features are likely to differ from the average person’s healthy lung or cervical cells. The researchers were astounded by how effective K777 was at preventing viral infection in the lab.
K777 has been licensed by Selva Therapeutics, a privately held biotechnology company, from UC San Diego. Parallel to this research, the company discovered that the experimental therapeutic prevented lung damage in COVID-19 animal models and was well tolerated by people who took part in Phase I clinical trial to assess safety. Selva intends to conduct a Phase IIa clinical trial in COVID-19 patients who are not hospitalized in late 2021.
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Reference:
- Drake M. Mellott, Chien-Te Tseng, Aleksandra Drelich, PavlaFajtová, Bala C. Chenna, Demetrios H. Kostomiris, Jason Hsu, Jiyun Zhu, Zane W. Taylor, Klaudia I. Kocurek, Vivian Tat, ArdalaKatzfuss, Linfeng Li, Miriam A. Giardini, Danielle Skinner, Ken Hirata, Michael C. Yoon, Sungjun Beck, Aaron F. Carlin, Alex E. Clark, Laura Beretta, Daniel Maneval, Vivian Hook, Felix Frueh, Brett L. Hurst, Hong Wang, Frank M. Raushel, Anthony J. O’Donoghue, Jair Lage de Siqueira-Neto, Thomas D. Meek, James H. McKerrow. A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells. ACS Chemical Biology, 2021; DOI: 10.1021/acschembio.0c00875
- University of California – San Diego. “Experimental therapy for parasitic heart disease may also help stop COVID-19.” ScienceDaily. ScienceDaily, 2 April 2021.
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