Development of mitochondria- and protease-specific prodrugs in the potential treatment of parasitic helminth infections

Oluwadare, Eyitayo; Rehan, Aiman; Ding, Yao; Turnbull, Agnes; Malone, Eva; Mincher, David; Proudfoot, Lorna

Abstract

Anthelmintic resistance and the shortage of new drugs represent an urgent need for the development of novel anti-parasite drugs with effective delivery to the target site. Reduced bioavailability and sub-optimal doses can be responsible for generation of anthelmintic resistance, so there is potential to convert proprietary products to new ‘smarter’ targetable prodrugs, which may circumvent developing resistance and lower general toxicity.
Caenorhabditis elegans has been used as a parasite model to demonstrate mitochondria- and protease-specific targeting. We have also been able to demonstrate the potential for protease-specific targeting in vitro in the case of Haemonchus contortus and Teladorsagia circumcincta. A series of novel targeted anthelmintic candidate drugs have been synthesized, based on a tubulin disrupting agent; tubulin is a known target of the benzimidazole anthelmintics. New prodrugs are ester-linked to a lipophilic cationic carrier that are designed to not only pass through cell membranes and localise in mitochondria but also facilitate drug cellular uptake by avoiding p-glycoprotein-type mediated efflux mechanisms. C. elegans L4 larvae were treated with mitochondria-specific prodrugs in a 24-well plate assay and the percentage survival was monitored after specific incubation times compared with controls. Preliminary biological evaluation of these prodrugs demonstrated significant toxicity against C. elegans. In the case of protease-specific prodrugs, we used a novel fluorogenic rhodamine-based asparagine-containing oligopeptide substrate (SM9) attached to a ‘black hole’ quencher where selective cleavage by the target protease separates the quencher from the probe, triggering fluorescence. With the SM9 probe, accumulation was detected as fluorescence in specific areas, particularly around neurons associated with the pharynx, vulva (HSN), neurosecretory-motor neuron and pre-anal ganglion regions. Protease-specific probe localization could potentially be exploited to achieve region-specific, protease-mediated prodrug activation and therefore site-specific drug delivery. Work will continue to refine and define structure-activity relationships and to determine the effect of the novel agents on worm viability.

Citation

Oluwadare, E., Rehan, A., Ding, Y., Turnbull, A., Malone, E., Mincher, D., & Proudfoot, L. (2016, September). Development of mitochondria- and protease-specific prodrugs in the potential treatment of parasitic helminth infections. Poster presented at Molecular & Cellular Biology of Helminth Parasites X, Hydra, Greece

• Presentation Conference Type: Poster
• Conference Name: Molecular & Cellular Biology of Helminth Parasites X
• Conference Location: Hydra, Greece
• Start Date: Sep 4, 2016
• End Date: Sep 9, 2016
• Deposit Date: Apr 17, 2018
• Keywords: parasitic helminth infections
• Public URL: http://researchrepository.napier.ac.uk/Output/1155750
• Related Public URLs: http://hydra.bio.ed.ac.uk/previous-conferences