Conference Agenda

Giardia duodenalis is a gastrointestinal parasite causing ~200 million symptomatic infections annually, disproportionately in lower socioeconomic tiers and children. Chemotherapeutic interventions are limited to nitroheterocyclic antibiotics such as metronidazole. However, high doses are toxic and drug-resistant treatment failures occur in up to 20% of cases, highlighting the urgency of novel and safer chemotherapeutics. Here, we target the disproportionate kinome of G. duodenalis with small-molecule inhibitors to reveal novel antigiardials and their molecular targets for next generation antiparasitics.

Using "Click" chemistry, we immobilised a potent drug-like kinase inhibitor to azide-agarose supports and identified a high-affinity kinase domain-containing protein (GiK5) as the putative target for this inhibitor. We validated recombinant GiK5-inhibitor engagement through differential scanning fluorimetry, native mass spectrometry and the fluorescent ADP-glo assay. Further, we conducted a multiplexed CRISPR-interference knockdown which showed lower GiK5 abundance at the protein level contributed to slower parasite growth, suggesting the likely essentiality of this protein in the parasite.

We reveal this likely druggable kinase in G. duodenalis and this workflow incentivises high-throughput, target-centric screening campaigns for structure-guided drug-discovery, as well as repurposing clinically-approved kinase inhibitors for chemotherapeutic interventions against this parasite.