Integrative structural biology in molecular parasitology: new strategies for old diseases
Résumé
Parasitic diseases are a major threat to human health, especially in countries in
which access to sanitation and treatment is extremely limited. Eradication of helminth
infections is one of the pillars of the recently launched WHO roadmap 2030 to attain
global health goals. Worms have evolved to evade the host immune response while
travelling through and residing in the host body. It is important for both diagnostics and
therapeutics, to know the molecular players in this survival game. In particular, for the
human parasite Schistosoma mansoni the methods of diagnosis are not able to detect
the early stages of infection and WHO mass drug administration relies on only one
drug. Therefore, the identification and characterization of key macromolecular targets
for diagnostic and drug discovery is of utmost importance.
Advances in genomics, proteomics and metabolomics have directed this task to
more rational and interdisciplinary strategies, where structural techniques, such as
macromolecular crystallography, SAXS and electron microscopy are pivotal. We are
integrating structural biology with bioinformatics, molecular biology, biochemistry,
biophysics and medicinal chemistry to select protein targets and to functionally and
structurally characterise them.
In the last fifteen years we have deposited 41 structures in the PDB on two main
subjects of research in our laboratories: (a) focussed structural genomics of the thiolmediated
detoxification metabolism; (b) structural characterization of the worm
secretome. In the former case we have elucidated the entire pathway and selected 2
candidates to perform cycles of structure-based drug design; in the latter the objective
is to understand what is at the interface between the worm and the host and to select
which macromolecules might become good diagnostics and/or vaccine candidates.
The information thus obtained is currently used to shed light on the challenging
biological questions opened by a vector-borne eukaryotic parasite that knows our
immune system and its regulation better than we do.