Tài liệu Báo cáo khoa học: Multi-targeted activity of maslinic acid as an antimalarial natural

Multi-targeted activity of maslinic acid as an antimalarial

natural compound

Carlos Moneriz1,4, Jordi Mestres2

, Jose´ M. Bautista1,3, Amalia Diez1,3 and Antonio Puyet1,3

1 Departamento de Bioquı´mica y Biologı´a Molecular IV, Facultad de Veterinaria, Universidad Complutense de Madrid, Spain

2 Chemogenomics Laboratory, Research Unit on Biomedical Informatics (GRIB), Institut Municipal d’Investigacio´ Me`dica and

Universitat Pompeu Fabra, Barcelona, Spain

3 Instituto de Investigacio´n del Hospital 12 de Octubre, Universidad Complutense de Madrid, Spain

4 Departamento de Bioquı´mica, Facultad de Medicina, Universidad de Cartagena, Colombia

Keywords

apicomplexa; merozoite surface protein;

metalloprotease inhibition; PfSUB1;

phospholipase; plasmodium

Correspondence

A. Puyet, Departamento de Bioquı´mica y

Biologı´a Molecular IV, Facultad de

Veterinaria, Universidad Complutense de

Madrid, E28040 Madrid, Spain

Fax: +34 913 943 824

Tel: +34 913 943 827

E-mail: [email protected]

(Received 21 April 2011, revised 14 June

2011, accepted 17 June 2011)

doi:10.1111/j.1742-4658.2011.08220.x

Most drugs against malaria that are available or under development target

a single process of the parasite infective cycle, favouring the appearance of

resistant mutants which are easily spread in areas under chemotherapeutic

treatments. Maslinic acid (MA) is a low toxic natural pentacyclic triterpene

for which a wide variety of biological and therapeutic activities have been

reported. Previous work revealed that Plasmodium falciparum erythrocytic

cultures were inhibited by MA, which was able to hinder the maturation

from ring to schizont stage and, as a consequence, prevent the release of

merozoites and the subsequent invasion. We show here that MA effectively

inhibits the proteolytic processing of the merozoite surface protein com￾plex, probably by inhibition of PfSUB1. In addition, MA was also found

to inhibit metalloproteases of the M16 family by a non-chelating mecha￾nism, suggesting the possible hindrance of plasmodial metalloproteases

belonging to that family, such as falcilysin and apicoplast peptide-process￾ing proteases. Finally, in silico target screening was used to search for other

potential binding targets that may have remained undetected. Among the

targets identified, the method recovered two for which experimental activity

could be confirmed, and suggested several putative new targets to which

MA could have affinity. One of these unreported targets, phospholipase

A2, was shown to be partially inhibited by MA. These results suggest that

MA may behave as a multi-targeted drug against the intra-erythrocytic

cycle of Plasmodium, providing a new tool to investigate the synergistic

effect of inhibiting several unrelated processes with a single compound,

a new concept in antimalarial research.

Introduction

As long as effective vaccines against malaria remain

unavailable, the search for new antimalarial drugs is

still required because of the incomplete protection

obtained with the present therapeutic methods and the

emergence of resistant strains in endemic regions. Most

present and prospective drugs against Plasmodium

falciparum, the causative agent of the most virulent

form of human malaria, have been designed to inter￾fere with essential processes at the blood stage of the

parasite [1], which accounts for the main clinical symp￾toms of disease. Despite the wide variety of potential

targets identified in the intra-erythrocytic cycle of

Abbreviations

IC50, half maximal inhibitory concentration; MA, maslinic acid; MSP, merozoite surface protein; PLA2, phospholipase A2; RBCs, red blood

cells; SERA, serine repeat antigen.

FEBS Journal 278 (2011) 2951–2961 ª 2011 The Authors Journal compilation ª 2011 FEBS 2951