Targeting Leishmania: exploring novel antileishmanial compounds and drug targets in the context of parasite cell death
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Abstract
Leishmaniasis is a neglected tropical disease with limited therapeutic options. This
thesis employed two complementary approaches and human primary cell models to
identify novel biological concepts which may contribute to therapeutic advancements.
In a series of phenotypic screenings, pateamines and arylmethylaminosteroids were identified
as chemical entities eliciting in vitro antileishmanial effects. While pateamines
exhibited excessive cytotoxicity towards host macrophages, both arylmethylaminosteroids
could significantly reduce intracellular parasite burden. Based on their activity,
authorized compounds fulfilling pharmacophore criteria were tested for antileishmanial
activity with an extraordinary hit rate. Repurposing of established drugs is a pragmatic
strategy to accelerate the development of new antiparasitic therapies.
As a second approach, putative drug targets in Leishmania major linked to cell death
were investigated. Many cellular processes in these parasites remain poorly characterized.
Programmed cell death is a potential drug target, as not only regulates parasite
survival and death but also facilitates immunosuppressive mechanisms. Genome editing
was employed to delete candidate genes hypothesized to be associated with this
process. However, no links to cell death pathways were discovered.
Instead, a quantitative proteomics study identified p1/s1, a 3’-nucleotidase/nuclease,
as enriched in sub-lethal stress and potentially involved in DNA degradation. Extensive
characterization of this versatile ecto-enzyme revealed no link to cell death,
but its dual activity was confirmed in an inducible knockout system. Degradation of
free 3’-nucleotides and nucleic acids by p1/s1 provides L. major with essential purines
while simultaneously facilitating immune evasion. Specifically, during in vitro infection,
3’-AMP hydrolysis led to decreased pro-inflammatory TNFα secretion and reduced
T cell proliferation via the generation of immunomodulatory adenosine. Furthermore,
p1/s1-mediated endonuclease activity enabled L. major to degrade and escape neutrophil
extracellular traps.
In summary, this thesis provides new insights into the molecular biology of Leishmania
and outlines several novel antileishmanial strategies, highlighting potential directions
for the development of future therapeutics.