Computational Design of Protein-Based Inhibitors of Plasmodium vivax Subtilisin-Like 1 ProteaseReportar como inadecuado




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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.



Autor: Giacomo Bastianelli, Anthony Bouillon, Christophe Nguyen, Dung Le-Nguyen, Michael Nilges , Jean-Christophe Barale

Fuente: http://plos.srce.hr/



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