Rational approach to drug discovery for human schistosomiasis
| Autor: | Stanton F. McHardy, Jayce Rhodes, Philip T. LoVerde, Sevan N. Alwan, Alexander B. Taylor, Frédéric D. Chevalier, Tim J. Anderson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Drug Regular article media_common.quotation_subject 030231 tropical medicine Schistosomiasis Drug resistance Computational biology Infectious and parasitic diseases RC109-216 Praziquantel Control programs 03 medical and health sciences 0302 clinical medicine Animals Humans Medicine Pharmacology (medical) media_common Schistosoma Pharmacology biology business.industry Drug discovery Sulfotransferase Schistosoma mansoni biology.organism_classification medicine.disease Oxamniquine 030104 developmental biology Infectious Diseases Drug development Parasitology business medicine.drug |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance, Vol 16, Iss, Pp 140-147 (2021) International Journal for Parasitology: Drugs and Drug Resistance |
| ISSN: | 2211-3207 |
| Popis: | 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. Graphical abstract Image 1 Highlights • Identification of gene for oxamniquine drug resistance. • Identify the mode of action of oxamniquine. • Develop an iterative approach to drug discovery. • Identify oxamniquine derivatives that will kill the three major species of Schistosoma. |
| Databáze: | OpenAIRE |
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