Structure-based drug design, synthesis and biological assays of P. falciparum Atg3–Atg8 protein–protein interaction inhibitors


The proteins involved in the autophagy (Atg) pathway have recently been considered promising targets for the development of new antimalarial drugs. In particular, inhibitors of the protein–protein interaction (PPI) between Atg3 and Atg8 of Plasmodium falciparum retarded the blood- and liver-stages of parasite growth. In this paper, we used computational techniques to design a new class of peptidomimetics mimicking the Atg3 interaction motif, which were then synthesized by click-chemistry. Surface plasmon resonance has been employed to measure the ability of these compounds to inhibit the Atg3–Atg8 reciprocal protein–protein interaction. Moreover, P. falciparum growth inhibition in red blood cell cultures was evaluated as well as the cyto-toxicity of the compounds.

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Protein–protein interactions


Molecular dynamics


Surface plasmon resonance


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We acknowledge the CINECA and the Regione Lombardia award under the LISA initiative, for the availability of high performance computing resources and support. We thank the Johns Hopkins Malaria Research Institute parasite and insectary facility for assistance with our experiments. This work was partially funded through The Bloomberg Family Foundation (J.B.). We thank Professors D. Taramelli and M. De Amici for helpful discussion. L. L. thanks the University of Pavia for partial financial support.

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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

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Correspondence to Giovanni Grazioso.

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Villa, S., Legnani, L., Colombo, D. et al. Structure-based drug design, synthesis and biological assays of P. falciparum Atg3–Atg8 protein–protein interaction inhibitors. J Comput Aided Mol Des 32, 473–486 (2018).

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  • Malaria
  • Autophagy
  • Atg8 inhibitors
  • Docking
  • PPI inhibitors
  • Peptidomimetics
  • 1,2,3-Triazole