Rational approach to drug discovery for human schistosomiasis
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 resist...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-08-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221132072100021X |
| _version_ | 1818718526426316800 |
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| author | Philip T. LoVerde Sevan N. Alwan Alexander B. Taylor Jayce Rhodes Frédéric D. Chevalier Timothy JC. Anderson Stanton F. McHardy |
| author_facet | Philip T. LoVerde Sevan N. Alwan Alexander B. Taylor Jayce Rhodes Frédéric D. Chevalier Timothy JC. Anderson Stanton F. McHardy |
| author_sort | Philip T. LoVerde |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T19:52:27Z |
| format | Article |
| id | doaj.art-719a25b8fb284e2380401b9a6d25e8f0 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-17T19:52:27Z |
| publishDate | 2021-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-719a25b8fb284e2380401b9a6d25e8f02022-12-21T21:34:41ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072021-08-0116140147Rational approach to drug discovery for human schistosomiasisPhilip T. LoVerde0Sevan N. Alwan1Alexander B. Taylor2Jayce Rhodes3Frédéric D. Chevalier4Timothy JC. Anderson5Stanton F. McHardy6Departments of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA; Pathology and Laboratory Medicine, The University of Texas Health Science Center, San Antonio, TX, USA; Corresponding author. Departments of Biochemistry and Structural Biology, USA.Departments of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USADepartments of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USACenter for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX, USAProgram in Host-Pathogen Interactions, Texas Biomedical Research Institute, San Antonio, TX, USAProgram in Disease Intervention and Prevention, Texas Biomedical Research Institute, San Antonio, TX, USACenter for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, TX, USAHuman 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.http://www.sciencedirect.com/science/article/pii/S221132072100021XSchistosomiasisDrug discoveryDrug resistanceControl programsSulfotransferaseOxamniquine |
| spellingShingle | Philip T. LoVerde Sevan N. Alwan Alexander B. Taylor Jayce Rhodes Frédéric D. Chevalier Timothy JC. Anderson Stanton F. McHardy Rational approach to drug discovery for human schistosomiasis International Journal for Parasitology: Drugs and Drug Resistance Schistosomiasis Drug discovery Drug resistance Control programs Sulfotransferase Oxamniquine |
| title | Rational approach to drug discovery for human schistosomiasis |
| title_full | Rational approach to drug discovery for human schistosomiasis |
| title_fullStr | Rational approach to drug discovery for human schistosomiasis |
| title_full_unstemmed | Rational approach to drug discovery for human schistosomiasis |
| title_short | Rational approach to drug discovery for human schistosomiasis |
| title_sort | rational approach to drug discovery for human schistosomiasis |
| topic | Schistosomiasis Drug discovery Drug resistance Control programs Sulfotransferase Oxamniquine |
| url | http://www.sciencedirect.com/science/article/pii/S221132072100021X |
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