Jacopo Novelli et al. (2007) International Worm Meeting "Mining the Brugia malayi genome for novel nematode drug targets."

Sanjay Kumar, Kshitiz Chaudhary, Jacopo Novelli, Clotilde Carlow, Yinhua Zhang, Jeremy Foster

[

International Worm Meeting,

2007]

Filarial parasites represent a major human health concern in developing countries. The paucity of functional data has hitherto hindered the development of new nematicidal drugs, which are urgently needed. The availability of complete genome sequences offers an unprecedented opportunity to fill the gap. A draft sequence of genome of the filiarial nematode Brugia malayi is now publicly available (http://www.tigr.org/tdb/e2k1/bma1/). We reasoned that this sequence could be mined for novel druggable genes by removing those conserved between nematodes and vertebrates, which would increase the risk of compound cross-toxicity, and by focusing on nematode-centric essential processes. By applying multiple layers of computational subtractive filtering, we weeded out genes with close homologs in vertebrates, and selected for genes having a C. elegans counterpart characterized by lethal or subviable RNAi phenotypes, which suggests essentiality. This approach yielded a list of nearly 600 Brugia potential drug targets. Based on the homology to the C. elegans genes, several Brugia targets appear to be involved in nematode-specific metabolic pathways, such as chitin synthesis, or physiological processes, such as molting. We are analyzing the function of the most promising targets in nematode development by inspecting the mutant phenotype of the C. elegans counterpart, by reporter gene analysis in C. elegans, by performing C. elegans-Brugia interspecies transgenic rescue experiments and by expressing and assaying the activity of the C. elegans and B. malayi recombinant proteins. Our analysis sheds light on novel essential aspects of nematode biology, opening new avenues for drug intervention. Progress in the molecular and biochemical characterization of the targets will be reported.

Bakowski MA et al. (2019) Sci Transl Med "Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections."

[

Sci Transl Med,

2019]

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.