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Antimicrobial Agents and Chemotherapy, November 1998, p. 2973-2977, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Central Role of Hemoglobin Degradation in
Mechanisms of Action of 4-Aminoquinolines, Quinoline Methanols,
and Phenanthrene Methanols
Mathirut
Mungthin,1
Patrick G.
Bray,1
Robert G.
Ridley,2 and
Stephen
A.
Ward1,*
Department of Pharmacology and Therapeutics,
The University of Liverpool, Liverpool L69 3BX, United
Kingdom,1 and
Pharmaceuticals Division,
Pharma Research Pre-Clinical, Hoffmann-La Roche, Basel,
Switzerland2
Received 17 June 1998/Returned for modification 6 August
1998/Accepted 26 August 1998
 |
ABSTRACT |
We have used a specific inhibitor of the malarial aspartic
proteinase plasmepsin I and a nonspecific cysteine proteinase inhibitor to investigate the importance of hemoglobin degradation in the mechanism of action of chloroquine, amodiaquine, quinine, mefloquine (MQ), halofantrine, and primaquine. Both proteinase inhibitors antagonized the antiparasitic activity of all drugs tested with the
exception of primaquine. An inhibitor of plasmepsin I, Ro40-4388, reduced the incorporation of radiolabelled chloroquine and quinine into
malarial pigment by 95%, while causing a 70% reduction in the
incorporation of radiolabelled MQ. Cysteine proteinase inhibitor E64
reduced the incorporation of chloroquine and quinine into malarial
pigment by 60 and 40%, respectively. This study provides definitive
support for the central role of hemoglobin degradation in the
mechanism of action of the 4-aminoquinolines and the quinoline and
phenanthrene methanol antimalarials.
| |
INTRODUCTION |
The 4-aminoquinolines chloroquine
(CQ) and amodiaquine (AQ), the quinoline methanols quinine (QN) and
mefloquine (MQ), and the phenanthrene methanol halofantrine (HF) all
exert selective toxicity towards the erythrocytic stages of malaria
parasites and were developed based on a knowledge of quinine structure
and activity (29, 31, 41). Although there are structural
similarities, QN, MQ, and HF are generally considered to constitute a
group distinct from CQ and AQ. This classification is based on a number of reported differences. The 4-aminoquinolines are diprotonated and
less lipid soluble at physiological pH, whereas the others, most
notably QN and MQ, are much weaker bases (26, 28, 50). Recent reports suggest an inverse relationship between parasite sensitivity to CQ and sensitivity to MQ, HF, and QN (22, 40, 44,
49). CQ and AQ induce pigment clumping in Plasmodium
berghei (24, 46). The quinoline methanols do not induce
pigment clumping but can inhibit 4-aminoquinoline-induced clumping
(20, 27, 30). Based on these observations and
spectrophotometric studies it has been suggested that the interactions
between the two drug classes and hematin are fundamentally different
(48, 49).
Morphological effects following treatment with MQ, QN, and HF are
similar to that observed following treatment with CQ, i.e., an initial
swelling of the acid food vacuole (20, 27, 30). It is
generally accepted that CQ (and AQ) exerts its antimalarial effects by
interacting with the hemoglobin degradation process within the
parasite, probably through an interaction with hematin (12, 33,
34), although the absolute mechanism of action is still debated
(1, 39, 45). The inhibition of hematin polymerization has
been used as a surrogate marker of 4-aminoquinoline type antimalarial
activities (12, 19, 32, 38), and MQ, QN, and HF, like CQ,
and AQ, can inhibit this process in vitro (12, 19, 39).
However, there are suggestions that an interaction with hematin
polymerization per se may not be enough to explain the activity of
drugs such as MQ (14). Although MQ and QN do interact with
free hematin, the interaction is relatively weak (6, 7, 12),
with correspondingly weaker inhibition of hematin polymerization
(12). MQ is a monoprotic weak base which should accumulate
less well than CQ; nevertheless, it shows similar 50% inhibitory
concentration (IC50) values in vitro. This evidence has
been the basis for questioning whether these drugs interact at
different points within the hemoglobin degradation process or if MQ has
an additional or an independent mechanism of action distinct from that
of AQ and CQ (10, 14).
Hemoglobin degradation within the parasite is an ordered process
(16, 18) involving at least three proteinases. Aspartic proteinase plasmepsin I is responsible for the initial cleavage of the
hemoglobin tetramer at the hinge position, the Phe33-Leu34 bond in the
-globin chain (17). A second aspartic proteinase, plasmepsin II, has also been identified and may have a role in the
cleavage of denatured hemoglobin (16). Falcipain, a cysteine proteinase, is also implicated in the cleavage of peptides from the
denatured hemoglobin (15, 16). The amino acids resulting from this process are presumably used by the parasite (37,
43). It is generally agreed that the remaining hematin residue,
which is potentially toxic, is removed via a polymerization process (11, 38), degradation, or export. Much evidence has
accumulated to support the hypothesis that quinoline type blood
schizontocides exert their antimalarial activity through interacting
with hematin (3, 8, 12, 42). We have recently extended these
observations and have provided strong evidence, in the case of CQ, that
both the mechanism of action and resistance in the parasite are based on drug access to hematin (5). Further, it has been reported that a specific inhibitor of malarial plasmepsin I, Ro40-4388, antagonizes the actions of CQ (25).
We have used Ro40-4388 and a nonselective inhibitor of cysteine
proteinase, E64, as probes to determine if the antimalarial activities
of QN, HF, MQ, AQ, and CQ all depend on the efficient degradation of
hemoglobin. Primaquine (PQ), an aminoquinoline antimalarial which does
not inhibit hematin polymerization (12, 19) and which
probably exerts its antimalarial action via a heme-independent
mechanism (12), was used as a control.
| |
MATERIALS AND METHODS |
Drugs used in the study.
CQ, AQ, QN, PQ, and
trans-epoxysuccinyl-L-leucylamido-(4-guanidino)-butane
(E64) were purchased from Sigma, Dorset, United Kingdom. MQ and
Ro40-4388 were obtained from Hoffmann-La Roche, Basel, Switzerland, and
HF was obtained from SmithKline Beecham.
Parasite isolates and cultivation.
A CQ-resistant isolate of
Plasmodium falciparum K1 and CQ-sensitive isolate HB3,
obtained from D. C. Warhurst, London School of Hygiene and
Tropical Medicine, London, United Kingdom, were used throughout this
study. Parasite cultures were maintained by an adaptation of the method
of Jensen and Trager (21). Cultures were synchronized by the
method of Lambros and Vandenburg (23) before use.
In vitro sensitivity assays.
Drug susceptibilities were
assessed by the measurement of [3H]hypoxanthine
incorporation into parasite nucleic acid as previously described by
Desjardins et al. (9). Drug IC50s were
calculated from the log of the dose/response relationship, as fitted
with Grafit software (Erithacus Software, Kent, United Kingdom).
Results are given as the means of at least three separate experiments.
Drug combination assays.
To analyze the combined effect of
the antimalarials and proteinase inhibitors (plasmepsin I inhibitor
Ro40-4388 and cysteine proteinase inhibitor E64) the IC50
for each drug alone was obtained as described above. From these values,
a stock solution of each drug was prepared such that the
IC50 of each drug would fall around the fourth serial
dilution. Combinations of the stock solutions were prepared in constant
ratios of 0:10, 1:9, 3:7, 5:5, 7:3, 9:1, and 10:0. Each combination was
serially diluted across a microtiter plate and processed as for the
standard sensitivity assay. The fractional inhibitory concentration
(FIC; FIC = IC50 of the drug in the
combination/IC50 of the drug when tested alone) of each
drug was calculated and plotted as an isobologram (4).
Hemozoin purification.
Ring stage parasites were incubated
for 24 h in the presence of radiolabelled drug and in the presence
or absence of a fixed concentration of proteinase inhibitor Ro40-4388
(300 nM) or E64 (10 µM). The HB3 isolate was used with
[3H]CQ (specific activity = 50.4 Ci/mmol) at a
concentration of 1 nM and with [3H]QN (specific
activity = 14.5 Ci/mmol) at a concentration of 7 nM. The K1
isolate was incubated with [3H]MQ (specific activity = 9.78 Ci/mmol) at a concentration of 5 nM. Hemozoin from the parasite
was purified with a sucrose cushion as previously described
(42). The cultures were pelleted and washed in RPMI 1640 twice, and the parasites were then lysed with 5 mM sodium phosphate, pH
7.5. The parasite lysate was pelleted and resuspended in 50 mM
Tris-HCl, pH 8.0. After sonication the sample was layered on top of a
1.7 M sucrose cushion in 50 mM Tris-HCl (1 ml), pH 8.0, followed by
ultracentrifugation at 200,000 × g for 15 min. The
pellet was then washed twice with 50 mM Tris-HCl, pH 8.0, and processed
for scintillation counting.
| |
RESULTS |
In vitro sensitivity of the parasites to antimalarial drugs and
proteinase inhibitors.
The IC50 data for all
antimalarial drugs tested and for proteinase inhibitors Ro40-4388 and
E64, indicative of their activities against CQ-resistant isolate K1 and
CQ-sensitive isolate HB3, are shown in Table
1. The ability of specific plasmepsin I
inhibitor Ro40-4388 to inhibit parasite growth is shown to be more
potent than that of cysteine proteinase inhibitor E64. The CQ-resistant and CQ-sensitive parasite isolates showed no differential
susceptibilities to these proteinase inhibitors. PQ displayed
antimalarial activity weaker than those of the other
quinoline-containing drugs used in this study.
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TABLE 1.
In vitro sensitivities of the K1 and HB3 isolates of
P. falciparum to the selected antimalarial drugs and
proteinase inhibitorsa
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|
The interaction between quinolines and proteinase inhibitors.
Representative isobolograms for antimalarial drug-proteinase inhibitor
combinations are shown in Fig. 1,
2, and 3.
The interactions between Ro40-4388 and CQ, AQ, MQ, and HF against the
K1 isolate were antagonistic (Fig. 1). Similar antagonism was observed
between E64 and these five drugs (Fig. 2). In contrast, the interaction between PQ and Ro40-4388 was additive (Fig. 3). Similar data were obtained with the HB3 isolate (data not shown).
The effect of proteinase inhibitors on the incorporation of
quinolines into hemozoin.
Incubation of ring stage parasites with
either radiolabelled CQ, QN, or MQ over 24 h resulted in
radiolabelled drug incorporation within the malarial pigment. Ro40-4388
at its IC50 reduced CQ and QN incorporation by more than
95% (Fig. 4A and B) and produced a 70%
reduction in MQ incorporation (Fig. 4C). E64 was less efficient in
reducing the incorporation of radiolabelled drugs (Fig. 4A and B). The
reductions produced by E64 at its IC50 were approximately 60% for CQ and 40% for QN. This effect of E64 is consistent with the
observations of Asawamahasakda et al. (1).
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FIG. 4.
(A) Incorporation of [3H]CQ into hemozoin
in the presence or absence of an inhibitor of plasmepsin I, Ro40-4388
(300 nM), or of cysteine proteinase, E64 (10 µM). Data represent
means ± standard deviations of five separate experiments; each
experiment was performed in triplicate with 2 × 109
parasitized erythrocytes. **, P < 0.05; ***,
P < 0.005. (B) Incorporation of [3H]QN into
hemozoin in the presence or absence of Ro40-4388 (300 nM) or E64 (10 µM). Data represent means ± standard deviations of five
separate experiments; each experiment was performed in triplicate with
2 × 109 parasitized erythrocytes. ****,
P < 0.001. (C) Incorporation of [3H]MQ into
hemozoin in the presence or absence of Ro40-4388 (300 nM). Data
represent means ± standard deviations of four separate
experiments; each experiment was performed in triplicate with 3 × 109 parasitized erythrocytes. **, P < 0.05.
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|
| |
DISCUSSION |
The malaria parasite needs to degrade hemoglobin for successful
growth and development. We believe that this is highlighted by the
ability of the two proteinase inhibitors used in this study to inhibit
parasite growth, as measured by the incorporation of hypoxanthine. The
IC50s of proteinase inhibitors Ro40-4388 and E64 in
P. falciparum presented here are comparable to those
reported earlier (2, 25). Cysteine proteinase inhibitor E64
has previously been shown to inhibit parasite growth at the trophozoite
stage, causing the accumulation of undegraded hemoglobin within the
food vacuole (2, 35, 36). E64 was shown to reduce the
formation of hemozoin via an inhibition of hemoglobin degradation
(1, 35), and this effect was irreversible (35).
In contrast, Ro40-4388 has been shown to inhibit the growth of P. falciparum parasites in vitro at nanomolar concentrations
(25). Interestingly, the inhibitory effects of Ro40-4388 on
hemozoin formation and parasite growth were reversible (unpublished
observations). The removal of inhibitor after 24 h of incubation
by minimal washing in complete medium was followed by pigment
production and parasite growth. This apparent parasitistatic effect may
have important implications for the use of these inhibitors as antimalarials.
Moon et al. (25) have shown that Ro40-4388 and CQ interact
antagonistically against P. falciparum. We have found
similar antagonism between Ro40-4388 and AQ, QN, MQ, and HF. These data suggest that all of the drugs tested have a common mechanism of action
based on some component of the hemoglobin degradation process. The fact
that [3H]QN and [3H]MQ are incorporated
into hemozoin in a manner similar to that of [3H]CQ
(42) lends support to this argument but does not provide conclusive proof. Since we have previously shown that Ro40-4388 produces a marked decrease in the number of binding sites, specifically for heme-binding drugs (5), we believe that the antagonism between Ro40-4388 and the quinolines and phenanthrenes is due to a
reduction in the amount of heme available for drug binding. Therefore,
the observation that the incorporation of a radiolabelled drug (CQ, QN,
or MQ) into the growing hemozoin polymers is almost completely arrested
in the presence of Ro40-4388 would suggest that it is the interaction
of the drug with the heme monomer or polymer which is central to
activity, rather than any secondary effect on heme polymerization. This
is in keeping with many of the hypotheses put forward to explain the
antimalarial activities of these drugs over the years (5, 7,
13) and argues against the need to invoke different mechanisms of
action for the 4-aminoquinolines and the quinoline or phenanthrene
methanols, as has been suggested (10, 14). The facts that PQ
does not inhibit hematin polymerization (12) and that it
most likely exerts its antimalarial action via a heme-independent
mechanism (12) give support to the use of PQ as a control in
this study. As predicted, there was no antagonism between PQ and
Ro40-4388. The observations of antagonism between the cysteine
proteinase inhibitor E64 highlight, we believe, the importance of the
cysteine proteinase falcipain in hemoglobin degradation and help to
further confirm the view that all of these drugs (CQ, AQ, QN, MQ, and
HF) exert their antimalarial effects via a common heme-dependent mechanism.
We have confirmed the incorporation of radiolabelled CQ into the
growing hemozoin reported initially by Sullivan et al. (42) and have extended these observations to QN and MQ. The fact that this
incorporation can be reduced with the proteinase inhibitors further
supports a role for hemoglobin degradation in their antimalarial activity. It could be argued that, as incorporation was reduced by
approximately 50% by E64 at its IC50, some of this effect
could be the indirect result of parasite death. However, exposure to this concentration of E64 for an equivalent period has been shown to
have little effect on hypoxanthine uptake (1) and, by
implication, on parasite viability.
The data presented here confirm the central and common role of
hemoglobin degradation in the mechanisms of action of the
4-aminoquinolines, the quinoline methanols, and the phenanthrene
methanols. This supports the view that all of these compounds are
acting through the same process without the need to invoke additional
targets. The data confirm that proteinase inhibition may be a rational target for antimalarial chemotherapy. If future strategies include the
use of these inhibitors in combination with other antimalarial drugs,
the antagonism seen here would argue against combinations with
quinoline type compounds.
| |
ACKNOWLEDGMENTS |
This work was supported by a research program grant from The
Wellcome Trust. M. Mungthin was supported by the Thai government and
Pramongkutklao College of Medicine.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pharmacology and Therapeutics, The University of Liverpool, P.O. Box 147, Liverpool L69 3BX, United Kingdom. Phone: 44-0151-794-8218. Fax:
44-0151-794-8217. E-mail: saward{at}liv.ac.uk.
| |
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0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
