Multi-targeted activity of maslinic acid as an antimalarial
natural compound
Carlos Moneriz
1,4
, Jordi Mestres
2
, Jose
´
M. Bautista
1,3
, Amalia Diez
1,3
and Antonio Puyet
1,3
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

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
IC
50
, half maximal inhibitory concentration; MA, maslinic acid; MSP, merozoite surface protein; PLA2, phospholipase A2; RBCs, red blood

parasites cultured in the presence of MA display
accumulation of ring, trophozoite or schizont intra-
erythrocytic forms. At low MA doses, the inhibition is
reversible, as removal of MA from the cultures relieves
this hindrance, allowing further maturation of the
parasite. The use of parasitostatic drugs has not been
investigated as a possible alternative or complement to
current drug therapies. Parasitostatic drugs may
enhance the host immune response by delaying the
infection progress and thus facilitating the presentation
of plasmodial antigens during the first infective stages,
therefore favouring the development of the acquired
immune response [16–18].
The actual target of MA on P. falciparum remains
to be investigated. MA does not hinder the formation
of hematin [15], discarding a possible interference
with the formation of hemozoin. Among the above
mentioned previously identified biological processes
affected by MA, the inhibition of proteases and ⁄ or
protein tyrosine phosphatases appears, a priori,as
potential targets for this compound in Plasmodium.
While little is known on protein tyrosine phosphatase
activities in P. falciparum, extensive work has been
devoted to finding and using specific inhibitors of Plas-
modium proteases. The main source of amino acids for
plasmodial protein synthesis derives from haemoglobin
degradation in the food vacuole by a process which
involves several proteases: plasmepsins, falcipains and
falcilysins. Plasmepsin II inhibitors have been devel-
oped based on the structure of the available inhibitors

ing using MA as ligand to predict its most probable
targets was performed, searching for enzymatic activi-
ties and protein binding structures which could eventu-
ally reveal new plasmodial target molecules for this
triterpene and novel strategies in malaria therapy.
Results and Discussion
Inhibition of proteases by MA
It has been previously proposed that MA may inhibit
the activity of proteases of T. gondii [14] and HIV
[12,31]. To ascertain the inhibition range of MA on
the different P. falciparum protease classes, in vitro
enzymatic assays were performed encompassing cyste-
ine, aspartic, serine and metalloproteases. The results,
shown in Table 1, indicate that MA is a strong inhibi-
tor of the metalloprotease thermolysin, showing also
Maslinic acid targets on Plasmodium falciparum C. Moneriz et al.
2952 FEBS Journal 278 (2011) 2951–2961 ª 2011 The Authors Journal compilation ª 2011 FEBS
low half maximal inhibitory concentration values
(IC
50
) for serine and cysteine proteases. Remarkably,
no inhibition was observed on the aspartic protease
pepsin. However, a possible specific inhibition of plas-
modial aspartic proteases could not be discarded, as
strong inhibition by MA on the HIV protease, which
belongs to the aspartic protease catalytic class, was
previously reported [12]. Accordingly, an additional
inhibition assay was performed using P. falciparum
protein extracts and including cathepsin D (an aspartic
protease) and the aspartic protease inhibitor pepstatin

[23] which may be further hydrolysed to free amino
acids outside the digestive vacuole [34,35]. It has been
shown that cysteine protease inhibitors, such as vinyl
sulfones, reduce the initial cleavage of globin peptides
in the trophozoite vacuole [36,37]. This effect has been
explained either by the direct inhibition of falcipain
[38] or by the indirect effect on the functionality of the
vacuole as a result of the accumulation of partially
hydrolysed peptides, leading to the accumulation of
uncleaved globin [39]. The possible effect, either direct
or indirect, of MA on globin hydrolysis was tested by
incubating synchronized ring-stage parasites with MA
or leupeptin, a cysteine protease inhibitor, and visuali-
zation of the globin band by SDS ⁄ PAGE. The results
did not show the characteristic accumulation of globin
in MA-treated cultures (Fig. 1), indicating that the ini-
tial hydrolysis of haemoglobin is not inhibited by MA.
In addition, the morphology of infected erythrocytes
incubated in the presence of MA is visibly different
from leupeptin-treated cultures. As can be seen in
Fig. 1B, the food vacuoles of parasites incubated 24 h
with leupeptin were abnormally dark-stained due to
the blockage in globin hydrolysis, while MA-treated
cultures showed abnormal trophozoite morphology
due to the growth arrest, but no accumulation of glo-
bin or vacuolization. These results confirm that MA
does not hinder the initial processing of globin and, in
consequence, it is unlikely that falcipains are targeted
by the drug.
Effect of MA on the activity of P. falciparum MSP

Table 2. Effect of MA on aspartic protease activity in P. falciparum
protein extracts. MA and pepstatin A were tested at 300 l
M.
Enzyme or total
protein extract Compound % Inhibition
Cathepsin D None 0
Pepstatin A 100
MA 6
Parasite None 0
Pepstatin A 100
Schizont MA 0
Leukocyte None 0
Pepstatin A 100
MA 15
C. Moneriz et al. Maslinic acid targets on Plasmodium falciparum
FEBS Journal 278 (2011) 2951–2961 ª 2011 The Authors Journal compilation ª 2011 FEBS 2953
role in the erythrocyte invasion by the parasite mero-
zoite through a mechanism involving the discharge of
PfSUB1 into the parasitophorous vacuole and the pro-
teolytic activation of SERA proteases, which are
required for merozoite egress [41,42]. An additional
role in the maturation of MSPs (MSP1, MSP6 and
MSP7) has also been recently reported for PfSUB1
[24]. MSPs are involved in the merozoite invasion of
erythrocytes [43]. PfSUB1 function is complemented
by the reported activity of PfSUB2, which performs a
secondary extracellular processing step on the MSP
complex [44]. Due to their similarity with subtilisin,
these subtilases may be expected to be inhibited by
MA. To verify this hypothesis, parasite proteins were

hindering invasion of new red blood cells (RBCs).
Chelation-independent protease inhibition by MA
As shown in Table 1, MA is a potent inhibitor of
thermolysin, a bacterial zinc metalloprotease belonging
to the M16 family [47]. Non-specific inhibition of
metalloprotease activity can readily be achieved by
chelating agents that bind to metal cations required in
the active site of the enzyme. The observed inhibition of
MA on thermolysin and PfSUB1, a calcium-dependent
serine protease, might then also be explained if MA
behaves as chelating agent on divalent cations. To test
this possibility, a colorimetric chelation assay was car-
ried out using zinc as divalent cation. As shown in the
Fig. 3, no significant chelation capacity was detected
for MA, even at higher concentrations than those used
in the treatments. This result shows that MA inhibits
metalloprotease and PfSUB1 activities by a specific,
non-chelating mechanism and also reinforces the
250
148
98
64
50
36
22
16
6
4
kDa
MW

or insulysin and pitrilysin [32], possibly involved in the
processing of apicoplast protein leader sequence.
Inhibition of any of these activities could contribute to
MA interference in the maturation of the parasite.
Polypharmacology of MA
The observed inhibition on PfSUB1 may contribute to
the arrest of P. falciparum infective cycle detected in
MA-treated cultures [15]. However, the morphology of
the blocked parasite cannot be completely explained
by inhibition of MSP1 processing. MSP1 is synthesized
from the onset of schizogony and is processed by
PfSUB1 at the time of merozoite egress from the
infected erythrocyte. It has been previously shown that
incubation of synchronic cultures with a highly specific
inhibitor of PfSUB1 produced no apparent effect on
pre-schizont stages, but rather a very specific inhibition
of schizont rupture and reduced invasion of the
released merozoites, which can be revealed by accu-
mulation of merozoite parasites in the cultures [41].
In contrast, cultures treated with MA display an
increased fraction of ring, trophozoite or schizont
stages [15], suggesting an additional inhibitory effect
early in the intra-erythrocytic cycle. The probable inhi-
bition of plasmodial metalloproteases by MA opens up
the possibility of a multi-targeted drug, interfering with
different parasite processes and leading to a blockage
of parasite maturation in the RBC from early ring to
schizont stages.
To further investigate the extent of possible multi-
targeted inhibitory activities of MA, a computational

Control
(12 h)
MA
(12 h)
Start schizonts (0 h)
kDa
O
O
O
HO
OH
HO
OH
OH
OH
HO
OH
OH
OH
HO
HO
CH
3
H
3
C
CH
3
CH
3

(CYP) isoform 2C8 has been reported to be actively
involved in drug efficacy due to its capacity to metab-
olize antimalarial drugs in humans [50]. On the other
hand, selective and irreversible inhibitors of mosquito
acetylcholinesterases for controlling malaria and other
mosquito-borne diseases have recently been described
[51]. Finally, even though the serotonin 5-HT2B
receptor subtype has not yet been specifically related
to malaria, there are reports linking serotonin recep-
tors in general as potential targets mediating differen-
tial chemical phenotypes in P. falciparum [52]. Given
the high levels of cross-pharmacology among amine
G-protein-coupled receptors [29], if some of them
have been linked already to malaria, the remaining
members of this subfamily could be relevant to
malaria as well.
Among the four novel putative targets identified,
MA was tested on PLA2, since it is the target showing
the highest predicted affinity. The results obtained are
collected in Table 4. As can be observed, MA inhibits
PLA2 in a dose-dependent manner up to 25% at
400 lm, which may be comparable to the 50% inhibi-
tion of PLA2 reported for other antimalarial drugs at
millimolar concentrations [49]. Accordingly, PLA2
may indeed be considered a new target for MA. The
inhibition of plasmodial PLA2, although incomplete,
can be related to the lipid metabolism and membrane
dynamics, contributing to the overall effect of this
compound on parasite maturation when combined
with the observed PfSUB1 and metalloprotease inhibi-

% zinc chelation
0
20
40
60
80
100
50
Fig. 3. Zinc chelating assay for MA. Percentage of zinc chelation
detected using Eriochrome Black T as an indicator of non-com-
plexed zinc cations. The assay was carried out by adding different
amounts of MA (black bars) or EDTA (grey bars) to a solution con-
taining 32 l
M Zn
2+
. Results are expressed as 100 · A
610 nm
(sam-
ple) ⁄ A
610 nm
(control without zinc).
Table 3. Results of the chemogenomic screening of proteins with
high probability of binding to MA.
Enzyme
MA predicted
affinity (l
M)
Phospholipase A2 3.2
Protein tyrosine phosphatase 4.0
CYP2C8 6.3

100% dimethylsulfoxide prior to assay.
In vitro cultures of P. falciparum
P. falciparum strain 3D7 (clone MRA-102) was provided
by The Malaria Research and Reference Reagent
Resource Center (MR4, deposited by DJ Carucci). Ery-
throcytes (RBC) were obtained from type A+ healthy
human local donors and collected in tubes with citrate-
phosphate-dextrose anticoagulant (Vacuette
Ò
Greiner Bio-
One GmbH, Kremsmu
¨
nster, Austria). The culture med-
ium consisted of standard RPMI 1640 (Sigma-Aldrich)
supplemented with 0.5% Albumax I (Life Technologies,
Paisley, UK), 100 lm hypoxanthine (Sigma-Aldrich),
25 mm HEPES (Sigma-Aldrich), 12.5 lgÆmL
)1
gentamicine
(Sigma-Aldrich) and 25 mm NaHCO
3
(Sigma-Aldrich).
Each culture was started by mixing uninfected and
infected erythrocytes to achieve a 1% haematocrit and
incubated in 5% CO
2
at 37 °C in tissue culture flasks
(Iwaki Asahi Glass, Tokyo, Japan). The progress of
growth in the culture was determined by microscopy in
thin blood smears stained with Wright’s eosin methylene

trations, were put into separate wells of a microplate. After
the addition of 50 lL of substrate working solution (1.57 mg
in 50% dimethylsulfoxide, 10 mm Tris ⁄ HCl, pH 7.8) the
plate was incubated at room temperature, protected from
light, for 60 min. The fluorescence intensity was measured at
485 nm excitation and 528 nm emission using a Perkin Elmer
LS-50B luminescence spectrophotometer. Background fluo-
rescence was subtracted from the inset data. Plots of percent-
age control activity versus concentration of inhibitor were
used to determine the concentrations that inhibited 50% of
protease activity. The enzymes evaluated, all purchased from
Sigma-Aldrich, were as follows: subtilisin A (
EC 3.4.21.62.)
from Bacillus licheniformis (serine protease), papain (
EC
3.4.22.2) from Carica papaya (cysteine protease), pepsin (EC
3.4.23.1) from porcine gastric mucosa (aspartic protease) and
thermolysin (
EC 3.4.24.27) from Bacillus thermoproteolyti-
cus rokko (metalloprotease). Assays were performed in
10 mm Tris ⁄ HCl (pH 7.8) except for pepsin, which was
assayed in 10 mm HCl (pH 1.8). Dilutions of papain were
made from a buffer containing 30 mml-cysteine.
The effect of MA on the activity of aspartic proteases
present in parasite protein extracts was assayed spectroflu-
orometrically with the internally quenched fluorescent
substrate MCA-G-K-P-I-L-F-F-R-L-K(DNP)-D-Arg-NH
2
trifluoroacetate salt (Sigma-Aldrich), which is not initially
fluorescent due to quenching of the 7-methoxycoumarin-4-

keha, WI, USA) at a 1 : 5000 dilution [24]. Detection was
performed using the Super Signal chemiluminescent substrate
(Thermo Fisher Scientific, Rockford, IL, USA) and exposure
to X-ray film. Finally, aliquots from cultures grown were also
examined microscopically.
Haemoglobin degradation assay
To assess the effect of MA on the haemoglobin accumula-
tion in trophozoites, synchronized ring-stage parasites at
10% parasitaemia were incubated at 37 °C in microtitre
plate cultures with MA (100 lm) or the cysteine proteinase
inhibitor leupeptin (100 lm) as a control. After 18 h of
incubation, Wright-stained smears were prepared from cul-
tures, and the parasites were evaluated for the presence of a
marked food vacuole abnormality that has been correlated
with a block in haemoglobin degradation [37,58]. To assess
haemoglobin accumulation, parasites cultured with inhibi-
tors as indicated were collected after 18 h incubation, and
proteins from parasite extracts were obtained as described
above, solubilized in electrophoresis sample buffer and elec-
trophoresed through 15% SDS ⁄ PAGE [36,37]. Proteins
were identified by staining the gel with Coomassie Blue.
In silico target screening
Our in silico target screening approach relies on the assump-
tion that the set of bioactive ligands collected for a given tar-
get provides a complementary description of the target from
a ligand perspective. In order to be able to process this infor-
mation efficiently, chemical structures need to be encoded
using some sort of mathematical descriptors. In this work,
three types of two-dimensional descriptors were used, namely
phrag, fpd and shed, each one of them characterizing chem-

plexometric indicator Eriochrome Black T (Sigma-Aldrich).
Samples were prepared by mixing 100 l L of 100 l m
ZnSO
4
.H
2
O, 200 lL of 0.3 m Na
2
CO
3
pH 10, 10 lL of com-
pound (MA or EDTA as control) and 6 lL of Eriochrome
Black T (5 mgÆmL
)1
in ethanol, pH 10). The pH of the Erio-
chrome Black T solution was adjusted by adding buffer solu-
tion dropwise until the colour changed from purple to blue.
200 lL of each sample were transferred to a 96-well micro-
plate and the absorbance was measured at 610 nm. Data
were expressed as a percentage of the increase in absorbance
caused by the removal of zinc cations due to chelating activ-
ity compared with a control without zinc. EDTA was used as
a positive control for chelating activity.
Acknowledgements
This work was supported by grants from the Spanish
Ministry of Education and Science (BIO2007-67885
and BIO2010-17039) and the Research Teams Consoli-
dation Programme of the UCM, Research Group
920267 and the Iberoamerican CYTED network No.
210RT0398. CM is supported by the Universidad de

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