Conference Agenda
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CP15: Drugs & Drug Resistance 2 - 10 min talks sponsored by Institute for Biomedicine and Glycomics, Griffith University Location: Lecture Theatre 1 Session Chair: Jacinta Macdonald, Griffith University Session Chair: Rohith Kutty, Griffith University | |
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The Plasmodium falciparum digestive vacuole is the site of action for second-generation bis-triazines and related antimalarial candidates 1: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Australia; 2: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Australia Widespread resistance to all current antimalarials threatens the control and eradication of malaria. Second-generation bis-triazines display low nanomolar potency and fast-killing asexual P. falciparum. However, the novel mechanism of action (MOA) remains unknown. In vitro combination drug-pulse assays using various inhibitors were performed to identify potential modulators of bis-triazine activity. We also included two antimalarial candidates currently under development with the Medicines for Malaria Venture (MMV) with some structural similarity to the bis-triazines. E64d, a cysteine protease inhibitor, bafilomycin A1, a V-ATPase inhibitor and chloroquine all caused antagonism of trophozoite-stage activity across the bis-triazine analogues and MMV candidates (between 2 and 10-fold increases in IC50). All three activity modulators are known to localise to the digestive vacuole and indicates potential involvement of the haemoglobin digestion pathway in the MOA of these series. 3-hour ring-stage survival assays with an artemisinin-resistant clinical isolate and a Pf3D7 line genetically modified to induce knockdown of essential falcipain-3 resulted in decreased activity (up to 20-fold increases in IC50) for both MMV candidates and one bis-triazine analogue. The current lead bis-triazine analogue, however, observed no change or slight hypersensitisation. Uninterrupted haemoglobin digestion appears to be vital for these compounds to maintain their fast-killing activity. | |