“Using functional genomics to support schistosome drug discovery.”

Hosts: Nicola Caldwell/ Beatriz Baragana

Venue: MSI Small Lecture Theatre, SLS

Abstract

Infection with blood fluke schistosomes causes schistosomiasis, one of the most devasting and chronically-debilitating neglected tropical diseases (NTD) on the planet. While most human infections still occur in sub-Saharan Africa, recent outbreaks in Europe demonstrate that this NTD is capable of expanding its range and establishing new endemic foci.

Regardless of geographical origin, schistosomiasis is primarily controlled by praziquantel (PZQ), a drug developed in the 1970s and transitioned as the front-line agent for mass drug administration programmes shortly thereafter. Due to the ever-present concern of PZQ-resistant/insensitive schistosomes developing, and in the absence of a deployable vaccine, new (replacement/complementary) drugs are urgently needed to achieve WHO elimination/eradication objectives.

Over the past 10 years, we have utilised phenotypic, whole-organism approaches to identify drug-like small molecules or natural products with anti-schistosomal activities as part of our drug discovery efforts. While the outputs of these ex vivo methods have led to the identification of incredibly-potent anti-schistosomal compounds, we routinely see substantial attrition of chemical matter prior to and during in vivo efficacy experiments in the murine model of schistosomiasis.

Using Schistosoma mansoni lysine demethylase 1 (SmLSD1) as an exemplar, I will demonstrate how both functional genomics- and chemical biology- approaches can be employed to improve selection and prioritisation of new anti-schistosomal targets. Deployment of these intersecting approaches together with orthogonal ones developed by our Dundee collaborators will improve our ability to effectively triage compound/target pairings and increase the pace and streamline the pathway of anti-schistosomal drug discovery.