TY - JOUR
T1 - Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8-Atg3 Protein-Protein Interaction
AU - Hain, Adelaide U P
AU - Miller, Alexia S.
AU - Levitskaya, Jelena
AU - Bosch, Jürgen
PY - 2016
Y1 - 2016
N2 - New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of-concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P.falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how insilico screening and structure-aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross-reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia.
AB - New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of-concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P.falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how insilico screening and structure-aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross-reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia.
KW - Autophagy
KW - Drug design
KW - Malaria
KW - Protein-protein interactions
KW - Virtual screening
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UR - http://www.scopus.com/inward/citedby.url?scp=84953931426&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201500515
DO - 10.1002/cmdc.201500515
M3 - Article
C2 - 26748931
AN - SCOPUS:84953931426
SN - 1860-7179
JO - ChemMedChem
JF - ChemMedChem
ER -