title: Computational design of protein-based inhibitors of Plasmodium vivax subtilisin-like 1 protease.
abstract: BACKGROUND
  Malaria remains a major global health concern. The development of novel therapeutic strategies is critical to overcome the selection of multiresistant parasites. The subtilisin-like protease (SUB1) involved in the egress of daughter Plasmodium parasites from infected erythrocytes and in their subsequent invasion into fresh erythrocytes has emerged as an interesting new drug target.
  
  
  RESULTS
  Using a computational approach based on homology modeling, protein-protein docking and mutation scoring, we designed protein-based inhibitors of Plasmodium vivax SUB1 (PvSUB1) and experimentally evaluated their inhibitory activity. The small peptidic trypsin inhibitor EETI-II was used as scaffold. We mutated residues at specific positions (P4 and P1) and calculated the change in free-energy of binding with PvSUB1. In agreement with our predictions, we identified a mutant of EETI-II (EETI-II-P4LP1W) with a Ki in the medium micromolar range.
  
  
  CONCLUSIONS
  Despite the challenges related to the lack of an experimental structure of PvSUB1, the computational protocol we developed in this study led to the design of protein-based inhibitors of PvSUB1. The approach we describe in this paper, together with other examples, demonstrates the capabilities of computational procedures to accelerate and guide the design of novel proteins with interesting therapeutic applications.
authors.affiliation: Institut Pasteur, Unité de Bioinformatique Structurale, Département de Biologie Structurale et Chimie, Paris, France; CNRS UMR 3528, Paris, France.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Bastianelli
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites, Département de Parasitologie et de Mycologie & CNRS URA 2581, Paris, France; CNRS, URA2581, Paris, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bouillon
authors.affiliation: SYSDIAG, CNRS UMR3145 CNRS-BioRad, Montpellier, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: SYSDIAG, CNRS UMR3145 CNRS-BioRad, Montpellier, France.
authors.forename: Dung
authors.initials: D
authors.lastname: Le-Nguyen
authors.affiliation: Institut Pasteur, Unité de Bioinformatique Structurale, Département de Biologie Structurale et Chimie, Paris, France; CNRS UMR 3528, Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Nilges
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites, Département de Parasitologie et de Mycologie & CNRS URA 2581, Paris, France; CNRS, URA2581, Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Barale
mesh_terms: D002384:Catalysis; D018360:Crystallography, X-Ray; D006801:Humans; D016780:Malaria, Vivax / Q000378:metabolism* / Q000473:pathology; D062105:Molecular Docking Simulation; D010966:Plasmodium vivax / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013381:Subtilisins / Q000737:chemistry* / Q000235:genetics
chemical_list: D015800:Protozoan Proteins; D013381:Subtilisins; C403176:subtilisin-like protease 1, Plasmodium falciparum