Since the onset of the COVID-19 pandemic, the novel coronavirus has led to 130 million diagnoses worldwide, with an associated 2.84 million deaths. While doctors and researchers are diligently working to develop vaccines and potential therapies, the virus is still running rampant. However, Dr. James McKerrow, MD, PhD, from UC-San Diego’s Skaggs School of Pharmacy and Pharmaceutical Sciences, may have come up with a potentially effective therapy for COVID-19 – after studying Chagas disease and other neglected tropical diseases.
According to Medical XPress, Dr. McKerrow works to understand, study, and treat neglected tropical diseases. Outside of Chagas disease, these include Dengue fever, filariasis, and river blindness, among others. Neglected tropical diseases are often under-studied; these parasitic infections tend to affect underserved or poor communities, particularly in poor or developing countries, many companies just do not tend to develop therapies. But now, Dr. McKerrow’s work evaluating potential treatments for Chagas disease could have determined a way to stop or inhibit the spread of COVID-19. Read the full study published in ACS Chemical Biology.
Also known as American trypanosomiasis, Chagas disease is a neglected tropical disease which affects many individuals throughout the Americas (in particular, Latin America). The Trypanosoma cruzi parasite causes Chagas disease. Typically, the parasite is spread through the triatomine bug, or the “kissing bug.” This aptly named creature sucks on the blood of humans and animals, passing along the parasite. However, blood transfusions, organ transplants, and birth may also transmit Chagas disease. The disease is named after Carlos Chagas, who first discovered the condition in 1909.
Overall, Chagas disease occurs in either an acute or chronic phase. In the acute phase, which happens right after infection, patients with Chagas disease have a ton of parasites in the blood. Altogether, this phase may last for a few weeks up to a few months. In some cases, patients are asymptomatic during the acute phase. However, those with symptoms may experience:
- Inflammation around the bite/infection site
- Appetite loss
- Nausea, vomiting, and diarrhea
- Headache and body aches
- Spleen and liver enlargement
- Swollen glands
- Romaña’s sign (swollen eyelids)
While some patients may feel better after the acute stage, the parasitic infection remains in the body if not treated. In the next phase (chronic), there are less – or no – parasites left in the blood. Again, some patients remain asymptomatic, but approximately 20-30% of patients will experience symptoms. Without treatment, these symptoms can be life-threatening. These include:
- Difficulty eating or defecating
- Colon, heart, and esophageal enlargement
- Heart failure
- Abnormal heart rhythm
- Cardiac arrest
Learn more about Chagas disease.
Through his research, Dr. McKerrow noted that Trypanosoma cruzi, the parasite which causes Chagas disease, replicates through the production of cruzain, an enzyme. In addition to helping the parasites spread, cruzain also assists T. cruzi in avoiding the immune system. Thus, Dr. McKerrow believed that cruzain inhibitors could prevent and treat Chagas disease.
K777 is one of the molecules which the research team discovered that is effective in inhibiting cruzain. The Drugs for Neglected Diseases Initiative (DNDI) describes K777 as:
a vinyl sulfone cysteine protease inhibitor, which inhibits cruzain, a key protease required for the survival of T. cruzi. K777 was originally characterized by the Sandler Center for Research in Tropical Parasitic Disease at UCSF and has since been shown to be safe and efficacious in animal models of acute and chronic Chagas disease.
K777 and COVID-19
During COVID-19 related research, researchers discovered that the spike protein helps the virus infect cells. However, research also showed that cathepsin L, an enzyme, played a role in assisting with this transmission. Now we know that cruzain and cathepsin L are very similar in looks and actions. Thus, researchers wondered whether cruzain inhibitors could also be affecting in stopping the spread and transmission of COVID-19.
Alongside his research team, Dr. McKerrow evaluated low doses of K777 for patients with COVID-19. Using cell lines derived from the epithelium of African green monkey kidneys, human lungs, and human cervical epithelium, researchers determined that K777 can inhibit cathepsin L. As a result, the cells are better protected from damage and it is more difficult to be infected with COVID-19. Additional research highlighted that K777 was also safe and effective in preventing lung damage in animal models of COVID-19.
Admittedly, researchers note that cell lines do not necessarily represent how the drug or virus will act in patients. Because they are lab-grown, their molecular and cellular features are not the same as average human cells sourced directly from patients. Additionally, K777 was more effective in cells which produced more ACE2 and cathepsin L, suggesting it might not be as effective in cells which produce less of these.
To learn more, UC-San Diego licensed K777 to biotechnology Selva Therapeutics (“Selva”). In the future, Selva hopes to evaluate K777 in a Phase 2a clinical trial for patients with COVID-19 who did not require additional hospitalization.