Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

Abstract

Onchocerciasis, or river blindness, is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus that affects more than 37 million people, mainly in third world countries. Currently, the only approved drug available for mass treatment is ivermectin, however, drug resistance is beginning to emerge, thus, new therapeutic targets and agents are desperately needed to treat and cure this devastating disease. Chitin metabolism plays a central role in invertebrate biology due to the critical structural function of chitin for the organism. Taken together with its absence in mammals, targeting chitin is an appealing therapeutic avenue. Importantly, the chitinase OvCHT1 from O. volvulus was recently discovered, however, its exact role in the worm’s metabolism remains unknown. A screening effort against OvCHT1 was conducted using the Johns Hopkins Clinical Compound Library that contains over 1,500 existing drugs. Closantel, a veterinary anthelmintic with known proton ionophore activities, was identified as a potent and specific inhibitor of filarial chitinases, an activity not previously reported for this compound. Notably, closantel was found also to completely inhibit molting of O. volvulus infective L3 stage larvae. Closantel appears to target two important biochemical processes essential to filarial parasites. To begin to unravel closantel’s effects, a retro-fragment-based study was used to define structural elements critical for closantel’s chitinase inhibitor function. As resources towards the development of new agents that target neglected tropical diseases are scant, the finding of an existing drug with impact against O. volvulus provides promise in the hunt for new therapies against river blindness.

Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans

“…Thus C. elegans has routinely been exploited as a more 'user-friendly' model system that is also highly tractable to molecular genetic techniques. However, the life-style of the free-living worm C. elegans is very different to that of the parasites, and therefore parasitologists have given careful thought to its relevance (Holden-Dye and Walker, 2012;Geary and Thompson, 2001). In terms of overall 'body plan' there is no doubt that all the species in the phylum Nematoda exhibit similarity despite their very different habitats.…”

Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

“…22 OvCHT1 is a larval-stagespecific chitinase that was recently identified as a potential biological target affecting nematode development. 23 As a result of a blind screening program, Closantel was discovered to be a potent and selective inhibitor of OvCHT1. Starting from this lead, a series of Closantel analogues was prepared to afford chitinase inhibitors with IC 50 values in the low nanomolar range.…”

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

“…This strategy is also finding increasing success in other laboratories (12)(13)(14)(15)(16) and resonates in part with the goals and related concept of diverted total synthesis (17,18). The starting point of FOS is function and the view that function could be emulated with a wide range of designed structures, as many structural types could mimic a natural product's shape and electron density features.…”