%0 Journal Article %T Computational Design of Protein-Based Inhibitors of Plasmodium vivax Subtilisin-Like 1 Protease %+ Bioinformatique structurale - Structural Bioinformatics %+ Immunologie moléculaire des parasites %+ Sysdiag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (SysDiag ) %A Bastianelli, Giacomo %A Bouillon, Anthony %A Nguyen, Christophe %A Le-Nguyen, Dung %A Nilges, Michael %A Barale, Jean-Christophe %Z This work was partly supported by MEST-CT-05-020311, a Marie Curie Early Stage Research Training Fellowship (EIMID) of the Framework Program 6 by the European Commission. AB is a fellow of the ‘‘Direction Generale pour l’Armement’’ from the French Ministry of Defense. This work was partly supported by the ‘‘Fond de ́die ́: combattre les maladies parasitaires’’ granted by Sanofi-Aventis and the French Ministry of Research and the Institut Carnot-Pasteur Maladies Infectieuses. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. SYSDIAG, CNRS UMR3145 CNRS-BioRad provided support in the form of salaries and operating costs for authors CN and DLN, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘‘author contributions’’ section. %< avec comité de lecture %@ 1932-6203 %J PLoS ONE %I Public Library of Science %V 9 %N 10 %8 2014-10-24 %D 2014 %R 10.1371/journal.pone.0109269 %M 25343504 %Z Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]Journal articles %X 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.Findings: 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. %G English %2 https://pasteur.hal.science/pasteur-01414431/document %2 https://pasteur.hal.science/pasteur-01414431/file/160%20NILGES%20-%20Pmid%2025343504.PDF %L pasteur-01414431 %U https://pasteur.hal.science/pasteur-01414431 %~ PASTEUR %~ CNRS