Year: 2021
Type: review
Abstract: Human schistosomiasis is a debilitating, life-threatening disease affecting more than 229 million people in as many as 78 countries. There is only one drug of choice effective against all three major species of Schistosoma, praziquantel (PZQ). However, as with many monotherapies, evidence for resistance is emerging in the field and can be selected for in the laboratory. Previously used therapies include oxamniquine (OXA), but shortcomings such as drug resistance and affordability resulted in discontinuation. Employing a genetic, biochemical and molecular approach, a sulfotransferase (SULT-OR) was identified as responsible for OXA drug resistance. By crystallizing SmSULT- OR with OXA, the mode of action of OXA was determined. This information allowed a rational approach to novel drug design. Our team approach with schistosome biologists, medicinal chemists, structural biologists and geneticists has enabled us to develop and test novel drug derivatives of OXA to treat this disease. Using an iterative process for drug development, we have successfully identified derivatives that are effective against all three species of the parasite. One derivative CIDD-0149830 kills 100% of all three human schistosome species within 5 days. The goal is to generate a second therapeutic with a different mode of action that can be used in conjunction with praziquantel to overcome the ever-growing threat of resistance and improve efficacy. The ability and need to design, screen, and develop future, affordable therapeutics to treat human schistosomiasis is critical for successful control program outcomes.
Language: English
Subfield: Parasitology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,840
Funders: U.S. Department of Energy, National Institutes of Health, Office of Science, University of Texas Health Science Center at San Antonio, Brigham Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory
Awards: G102163711, G107546177, Mays Cancer Center at UT Health SA, G1313983767, G1386414003, G16051329, G1664757510, San Antonio Biomedical Education and Research, G2287611682, G2498632753, G262962599, Structure-guided redesign of an antischistosomal drug, G2849897711, G3075337988, G32573923, G3330332559, G3874765150, G3924411600, G409777406, G4155925329, G4429385918, G498139845, Pixel Array Detector for Macromolecular Crystallography, G5607048534, G6717274789, G6848031779, G6918803902, G78868261, G8064967943, G8500532866, G9000051782, G9000324485, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W3168825341