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Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections
- Source :
- Science Translational Medicine, Science Translational Medicine, American Association for the Advancement of Science, 2019, 11 (491), pp.eaav3523. ⟨10.1126/scitranslmed.aav3523⟩
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targetsWolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination ofWolbachiain the in vivoLitomosoides sigmodontisfilarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantifyWolbachiaelimination inBrugia pahangifilarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed inL. sigmodontis,Brugia malayi, andOnchocerca ochengiin vivo preclinical models of filarial disease and in vitro selectivity againstLoa loa(a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.
- Subjects :
- 0301 basic medicine
Brugia pahangi
[SDV]Life Sciences [q-bio]
030231 tropical medicine
Brugia malayi
Small Molecule Libraries
03 medical and health sciences
Mice
0302 clinical medicine
In vivo
parasitic diseases
Drug Discovery
medicine
Animals
Filarioidea
ComputingMilieux_MISCELLANEOUS
Doxycycline
biology
General Medicine
biology.organism_classification
Virology
In vitro
3. Good health
Anti-Bacterial Agents
Filariasis
High-Throughput Screening Assays
Disease Models, Animal
030104 developmental biology
Phenotype
Quinazolines
Wolbachia
Female
Loa loa
Ex vivo
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19466234 and 19466242
- Database :
- OpenAIRE
- Journal :
- Science Translational Medicine, Science Translational Medicine, American Association for the Advancement of Science, 2019, 11 (491), pp.eaav3523. ⟨10.1126/scitranslmed.aav3523⟩
- Accession number :
- edsair.doi.dedup.....f5b7dd2acbde369889842c0450e10664
- Full Text :
- https://doi.org/10.1126/scitranslmed.aav3523⟩