Rational approach to drug discovery for human schistosomiasis

LoVerde, Philip T.; Alwan, Sevan N.; Taylor, Alexander B.; Rhodes, Jayce; Chevalier, Frédéric D.; Anderson, Timothy J. C.; McHardy, Stanton F.

doi:10.1016/j.ijpddr.2021.05.002

Rational approach to drug discovery for human schistosomiasis

Journal Article · Fri Jun 04 00:00:00 EDT 2021 · International Journal for Parasitology, Drugs and Drug Resistance

DOI:https://doi.org/10.1016/j.ijpddr.2021.05.002· OSTI ID:1808131

^[1]; Alwan, Sevan N. ^[1]; ^[1]; Rhodes, Jayce ^[1]; Chevalier, Frédéric D. ^[2]; Anderson, Timothy J. C. ^[2]; McHardy, Stanton F. ^[1]

Univ. of Texas at San Antonio, TX (United States)
Texas Biomedical Research Institute, San Antonio, TX (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1808131

Journal Information:: International Journal for Parasitology, Drugs and Drug Resistance, Journal Name: International Journal for Parasitology, Drugs and Drug Resistance Vol. 16; ISSN 2211-3207

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
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control programs
drug discovery
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Rational approach to drug discovery for human schistosomiasis

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