Research ArticlePARASITIC DISEASES

Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaav3523
DOI: 10.1126/scitranslmed.aav3523

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Walloping Wolbachia with quinazolines

A variety of adult parasitic worms depend on the bacterial endosymbiont Wolbachia for reproduction and survival, so Wolbachia is a clinical target for treating filarial nematodes. Antibiotics effective against Wolbachia require weeks of treatment and are not suitable for all patients. Bakowski et al. therefore performed a high-throughput phenotypic screen to look for alternative antiwolbachial compounds, which led them to quinazolines. Lead compounds were optimized and showed efficacy in multiple mouse filarial models, performing well or even better than 2 weeks of antibiotics. Their results suggest that a short course of quinazolines could eradicate Wolbachia, potentially eliminating adult worms in infected humans.

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 targets Wolbachia, 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 of Wolbachia in the in vivo Litomosoides sigmodontis filarial 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 quantify Wolbachia elimination in Brugia pahangi filarial 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 in L. sigmodontis, Brugia malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease and in vitro selectivity against Loa 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.

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