A drug repurposing screen for whipworms informed by comparative genomics

Abstract

Hundreds of millions of people worldwide are infected with the whipwormTrichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested theseex vivoby assessing motility of adult worms ofTrichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of≤50μM againstT. muris ex vivo, and selected nine for testingin vivo. However, the best worm burden reduction seen in mice was just 19%. The high number ofex vivohits againstT. murisshows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug repurposing against whipworms. Therefore, we recommend that prior toin vivostudies, future researchers first assess drug absorption by the host, for example, using human intestinal organoids or cell lines, and drug uptake by whipworms using intestinal organoids infected withT. muris.

High-throughput screening of more than 30,000 compounds for anthelmintics against gastrointestinal nematode parasites

“…Phenotypic screening using GIN parasites for anthelmintic has included screening against ex vivo adult parasites, egg hatch assay, larval stages, and infective third-stage larvae 32 . However, regarding GINs that infect humans, the throughput of these screens has been limited [32][33][34][35] . The free-living nematode Caenorhabditis elegans has been used as a surrogate model for GINs that infect humans 32,[36][37][38][39] .…”