Journal of Computer-Aided Molecular Design

, Volume 32, Issue 3, pp 473–486 | Cite as

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

  • Stefania Villa
  • Laura Legnani
  • Diego Colombo
  • Arianna Gelain
  • Carmen Lammi
  • Daniele Bongiorno
  • Denise P. Ilboudo
  • Kellen E. McGee
  • Jürgen Bosch
  • Giovanni GraziosoEmail author


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.


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





Protein–protein interactions


Molecular dynamics


Surface plasmon resonance



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.

Author contributions

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

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

10822_2018_102_MOESM1_ESM.pdf (657 kb)
Supplementary material 1 (PDF 656 KB)
10822_2018_102_MOESM2_ESM.pdf (2.3 mb)
Supplementary material 2 (PDF 2329 KB)


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Dipartimento di Scienze FarmaceuticheUniversità degli Studi di MilanoMilanItaly
  2. 2.Dipartimento di ChimicaUniversità degli Studi di PaviaPaviaItaly
  3. 3.Dipartimento di Biotecnologie Mediche e Medicina TraslazionaleUniversità degli Studi di MilanoMilanoItaly
  4. 4.Dipartimento di Scienze Farmacologiche e BiomolecolariUniversità degli Studi di MilanoMilanoItaly
  5. 5.Centre Universitaire PolytechniqueUniversité de OuagagadougouFada N’GourmaBurkina Faso
  6. 6.Pediatric Pulmonology Division, Department of PediatricsCase Western Reserve University School of MedicineClevelandUSA
  7. 7.InterRayBio, LLCBaltimoreUSA

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