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.

Structure-based drug design, synthesis and biological assays of P. falciparum Atg3-Atg8 protein-protein interaction inhibitors / S. Villa, L. Legnani, D. Colombo, A. Gelain, C. Lammi, D. Bongiorno, D.P. Ilboudo, K.E. Mcgee, J. Bosch, G. Grazioso. - In: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN. - ISSN 0920-654X. - 32:3(2018 Mar 01), pp. 473-486. [10.1007/s10822-018-0102-5]

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

S. Villa
Primo
;
L. Legnani
Secondo
;
D. Colombo;A. Gelain;C. Lammi;D.P. Ilboudo;G. Grazioso
Ultimo
2018

Abstract

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.
1,2,3-Triazole; Atg8 inhibitors; Autophagy; Docking; Malaria; Peptidomimetics; PPI inhibitors; Drug Discovery3003 Pharmaceutical Science; Computer Science Applications1707 Computer Vision and Pattern Recognition; Physical and Theoretical Chemistry
Settore CHIM/08 - Chimica Farmaceutica
1-mar-2018
30-gen-2018
Article (author)
File in questo prodotto:
File Dimensione Formato  
46.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.98 MB
Formato Adobe PDF
1.98 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
2018 JCompAidMolDes -preprint.pdf

accesso aperto

Descrizione: Articolo completo
Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 1.15 MB
Formato Adobe PDF
1.15 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/551211
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 9
social impact