Comparative properties of plasmepsins from the
Abstract
The devastating malaria, caused by parasites of the genus Plasmodium, afflicts nearly half of the world's population and imposes a heavy socio‐economic burden particularly to the disease‐endemic Sub‐Saharan Africa. Sustained efforts in malaria control have been made from the perspectives of medicine‐ and vaccine‐based prevention and treatment of malaria and malaria transmission blockage for the past 15 years, resulting in a decreased mortality rate by 60% and a decreased malaria incidence rate by 37% globally. Nonetheless, due to the emergence and rapid spread of drug‐resistant parasite strains, novel antimalarial drugs are urgently required to combat this deadly disease. Plasmepsins are deemed potential targets for novel antimalarial drug design. Plasmepsins represent an aspartic proteinase family that can be sub‐categorized into seven groups based on the amino acid sequence identity. This chapter discusses our progress in understanding the biosynthesis, biological functions and enzymatic characteristics of the plasmepsin family. This led to development of various types of plasmepsin‐targeted compounds and the assessment of their binding affinity and selectivity, anti‐parasitic activity and cytotoxicity. The gained experience and current status in developing plasmepsin‐targeted antimalarial drugs are addressed. Finally, a deeper and broader investigation on the functions and characteristics of the plasmepsin family is encouraged.
Keywords
- malaria
- plasmepsin
- drug design
- Plasmodium
- aspartic proteinase
1. Introduction
Malaria, a life‐threatening infectious disease, afflicts approximately 3.2 billion people, causes 214 million clinical cases and leads to nearly 440,000 deaths worldwide in 2015 despite the facts that malaria mortality rates decreased by 60% globally and by 66% in Africa between 2000 and 2015, and that malaria incidence rates decreased by 37% globally and by 42% in Africa for the past 15 years [1, 2]. Nearly 90% of the malaria cases and deaths occur in Sub‐Saharan Africa in 2015, loading a heavy socio‐economic burden to this poorly developed region [1].
Malaria is caused by parasitic protozoa of the genus
To complete its life cycle, the malaria parasite requires a female mosquito as the transmission vector and a vertebrate host (Figure 1). When a blood meal is taken, a parasite‐infected mosquito inoculates sporozoites into the human host to start the exo‐erythrocytic phase, in which sporozoites infect hepatocytes and mature into schizonts. Of note, in parasites such as
Malaria control in the modern era arguably starts from the isolation of antimalarial quinine and quinidine from cinchona bark in early nineteenth century [3], while it was not until 1925 that pamaquine (also known as plasmoquine or plasmochin), the first synthetic antimalarial drug, was yielded. Synthesized in 1934, chloroquine (CQ), a 4‐aminoquinoline compound, exhibited a strong antimalarial potency and a low toxicity and became the most extensively used drug in malaria prophylaxis and treatment between 1940s and 1960s [4–6]. The massive use of CQ, however, resulted in the emergence of CQ‐resistant
A major challenge faced by the anti‐malaria campaign currently is the emergence and rapid spread of drug‐resistant variants of
This review focuses on the biosynthesis, biological functions and enzymatic characteristics of the plasmepsin (PM) family from human malaria parasites. The progression of PM‐targeted antimalarial drug development is also discussed.
2. Plasmepsin family overview
From comparative genomic analysis of sequence information of seven
PM | Chr. | Pro | Zymogen | Mature enzyme | ||||||
---|---|---|---|---|---|---|---|---|---|---|
# a.a. | # a.a. | % i.d. | MW (Da) | pI | # a.a. | % i.d. | MW (Da) | pI | ||
PM1 | 14 | 123 | 452 | 62 | 51,461 | 7.23 | 329 | 70 | 37,050 | 4.82 |
PM2 | 14 | 124 | 453 | 61 | 51,481 | 5.29 | 329 | 69 | 36,915 | 4.62 |
HAP | 14 | 123 | 451 | 52 | 51,694 | 8.23 | 328 | 59 | 36,979 | 4.97 |
PM4 | 14 | 121 | 449 | — | 51,047 | 5.19 | 328 | — | 36,955 | 4.38 |
PM5 | 13 | 83 | 590 | 25 | 68,481 | 7.66 | 440 | 25 | 50,844 | 6.50 |
PM6 | 3 | 84 | 432 | 29 | 49,434 | 7.75 | 348 | 29 | 39,352 | 6.44 |
PM7 | 10 | 76 | 450 | 28 | 52,329 | 8.44 | 374 | 28 | 43,317 | 6.09 |
PM8 | 14 | 45 | 385 | 26 | 44,255 | 9.38 | 340 | 29 | 38,976 | 8.85 |
PM9 | 14 | 212 | 627 | 27 | 74,184 | 9.63 | 402 | 25 | 46,970 | 9.28 |
PM10 | 8 | 232 | 573 | 30 | 65,115 | 5.22 | 341 | 29 | 38,604 | 5.38 |
Of note,
3. Biosynthesis
3.1. Food vacuole plasmepsins
FV
To gain catalytic activity, FV PMs need to release their pro‐segments. The cleavage site is conserved at the motif (Y/H)LG* (S/N)XXD (* represents the scissile bond) [50], which is different from the sites where
Where does the maturation of FV PMs occur? Evidence from immunoEM shows that antibodies directed against N‐terminal epitopes of mature
The four FV
No studies, to the author's knowledge, have been reported on biosynthesis of the FV PMs from non‐
3.2. Non-food vacuole plasmepsins
Among the non‐FV PMs, PM5 is the most studied.
Few studies have addressed the biosynthesis of PMs 6–10. Genes encoding
4. Biological function
4.1. Hemoglobin digestion and degradation
The primary pathological role that FV PMs play is digestion and degradation of the oxygen‐carrying hemoglobin that constitutes 95% of cytosolic proteins of human red blood cells (Figure 3).
In the intra‐erythrocytic phase, hemoglobin digestion and degradation is carried out between the ring and the early schizont stage [70, 71]. A vast majority of hemoglobin, at a millimolar concentration in erythrocytes, however, is processed within the 6–12‐hour trophozoite stage [72], indicative of an enzyme‐catalyzed event. The processing of hemoglobin occurs mainly in FVs; however, it is also carried out in vesicles arising either from micropinocytosis of cytoplasm of host cells or from endocytosis of cytostomes [57].
Early investigations establish that aspartic and cysteine proteinase activities are responsible for hemoglobin processing [73–81]. The successful isolation of FV from cultured trophozoites renders possible identification of naturally‐occurring hemoglobin‐processing enzymes [82].
The purpose of hemoglobin digestion and degradation has been under debate. Some believe that malaria parasites consume hemoglobin as a source of nutrients [87–91], which is supported by their limited capacity to
4.2. Cytoskeletal protein processing and host cell remodeling
4.3. Ookinetes midgut invasion and oocyst development
PM4 (
Of particular note, antibodies directed against the catalytic domain of either
4.4. Host‐targeted protein export
In the intra‐erythrocytic phase, malaria parasites express and export hundreds of proteins, collectively named the “exportome,” to infected red blood cells in order to acquire nutrients, to remodel the host cell, to avoid host immune detection, and to promote virulence [100–102]. A portion of the exportome shares at the N‐terminus a pentameric sequence motif of RxLxE/Q/D (x represents any natural amino acid), known as the
PM5‐mediated PEXEL cleavage is proved to be essential to not only protein export but also parasite survival in that episomal expression of a catalytically inactive PM5 mutant decreases the level of proteins exported to host cells and slows down the parasite growth rate [64]. Interestingly, when the PEXEL motif of the
Of particular note, the host‐targeted malaria protein export is not restricted in the intra‐erythrocytic phase but occurs over the course of the parasite life cycle [66, 106, 107], which coincides with the spatio‐temporal expression pattern of PM5 [44, 65, 66]. It is thus conceivable that PM5 is also involved in protein export at other stages of the parasite life cycle, though no supporting evidence has been reported yet.
4.5. Other functions
Recent studies from Spaccapelo and colleagues showed the role of PM4 (
In another study [110], recombinant
5. Enzymatic characterization
5.1. Food vacuole plasmepsins
5.1.1. Plasmodium falciparum plasmepsin 1
The naturally‐occurring
The subsite specificity of
5.1.2. Plasmodium falciparum plasmepsin 2
The naturally‐occurring
Unlike the case of
Beyer and colleagues studied the subsite specificity of
5.1.3. Plasmodium falciparum histo-aspartic proteinase
HAP is a PM with the catalytic aspartic acid of the N‐terminus replaced by a histidine. Naturally‐occurring
Catalytically active
A key question remains elusive is whether
5.1.4. Plasmepsin 4 orthologs
To the author's knowledge, no literatures have thus far reported the characteristics of naturally‐occurring
Recombinant PM4s from the other three human malaria parasites and the rodent malarial parasite
5.2. Non-food vacuole plasmepsins
Thus far, enzymatic characterization of non‐FV PMs has been focused on the PM5 orthologs. PM5 (
Two constructs of
The enzymatic properties of PMs discussed in this section are summarized in Table 2.
PM | Expression pattern | Subcellular locationa | Enzymatic characteristics | |||
---|---|---|---|---|---|---|
pHb | Natural substrates | Subsite specificityd | Pepstatin A inhibition | |||
Intra‐erythrocytic phase; merizoites; gametocytes | FV, TV | 5.0 | Hb | FSF*L(Q/S)F | <1 nM ( | |
Intra‐erythrocytic phase; merizoites; gametocytes; oocysts; sporozoites | FV, TV | 4.7; ~6.8 | Hb; Host cytoskeletal proteins | nLInL*LQI | <1 nM ( | |
Intra‐erythrocytic phase; merizoites; gametocytes; sporozoites | FV, TV | 5.7 | Hb | n.d. | 1 μM (fully inhibition) | |
Intra‐erythrocytic phase; merizoites; gametocytes; oocysts; sporozoites | FV, TV | 4.5; ~6.6 | Hbc; Host cytoskeletal proteinsc | IQF*YIL | <1 nM ( | |
Intra‐erythrocytic phase | FV, TV | 4.5 | Hbc | LEF*FII | <1 nM ( | |
n.d. | FV, TV | 4.5 | Hbc | FEF*YFI | <1 nM ( | |
n.d. | FV, TV | 4.5 | Hbc | FEF*FII | <1 nM ( | |
n.d. | FV, TV | 5.0–5.5 | Hbc; Host cytoskeletal proteins | FEF*nLSW | <1 nM ( | |
Intra‐erythrocytic phase; merizoites; gametocytes; sporozoites | ER/NE | 6.0–6.5 | PEXEL‐containing parasite proteins | RxL*x(Q/E/D); RxL*xxE | ~20–30 µM (IC50) |
6. Plasmepsin-targeted antimalarial drug development
6.1. Evaluation of food vacuole plasmepsins as antimalarial drug targets
The establishment of the role of FV PMs in hemoglobin processing raised the question whether FV PMs can be targets of novel antimalarial drugs. Peptidomimetic compounds developed in the early stage (e.g., pepstatin A, SC‐50083, Ro40‐4388, and HIV‐1 PIs) bind FV PMs tightly and block growth of cultured parasites [46, 51, 140, 141], suggesting that inhibition of FV PMs is a promising antimalarial strategy. Numerous types of FV PM‐targeted compounds, synthetic or isolated from natural sources, have been assessed for the past two and a half decades based on criteria involving binding affinity and selectivity, inhibition potency to cultured parasite growth, and cytotoxicity to mammalian cell culture (for reviews, see for example [142, 143]). For example, certain hydroxyethylamine derivatives inhibit
To assess whether FV PMs are appropriate drug targets,
To better understand the relationship between enzyme inhibition and anti‐parasitic activity, the effects of known FV PM inhibitors on the growth of PM‐knockout parasites were investigated. When pepstatin A was administered to cultured parasite in the intra‐erythrocytic phase, growth of the Δ
Despite that FV PMs are not critical to parasite survival at the blood stage and that certain FV PM inhibitors exhibit their anti‐parasitic activities with an off‐target effect, it is still early to negate FV PM‐targeted drug design given our limited understanding of their functions and characteristics. The continuously identified novel functions of FV PMs plus their broad spatio‐temporal expression pattern over the course of the parasite life cycle are worthy of further investigation.
6.2. Developing novel antimalarial drugs targeting non-food vacuole plasmepsins
PM5 has been considered an ideal target for novel antimalarial drug design based on a series of findings: first, ablation of the gene encoding PM5 is lethal to cultured
Two basic components were incorporated in the initial design of PM5 inhibitors: a PEXEL sequence, which provides a moderate fit of compounds to the active site of the enzyme, and a transition‐state peptidomimetic moiety, which gives rise to a tight interaction with the catalytic residues of proteinases. WEHI‐916, a statine‐based compound mimicking the non‐prime‐side RVL motif of the PEXEL, shows a strong inhibition (IC50 = ~20 nM) of
Our limited knowledge on PMs 6–10 makes it difficult to assess the necessity and importance of developing drugs targeting these enzymes. However, the detection of these PMs in multiple stages of the parasite life cycle suggests that their role in malaria pathogenesis is non‐trivial. For future PM‐targeted drug development, the functions and characteristics of PMs 6‐10 warrant further study.
7. Concluding remarks
Malaria, one of the deadliest infectious diseases in history, still poses a serious socio‐economic problem at present. Malaria control has been effectively undertaken from multiple perspectives, including drug‐based disease prevention and treatment, intervention of malaria transmission by the mosquito vector, and usage of vaccine against malaria parasites. Though, the emergence and quick spread of drug‐resistant parasite strains urges us to identify new antimalarial drug targets. The subject of this review has focused on the aspartic proteinase PM family, the molecular entities deemed novel and promising targets of next‐generation antimalarial drugs.
Discussed here is our understanding of the PM family members on their biosynthesis, biological functions and characteristics for the past two and a half decades. Seven groups of PMs have thus far been identified from genome comparison of a series of
On the other hand, our knowledge on PMs is still quite limited and much needs to be clarified and explored in the future studies. For example, what is the biological meaning of the presence of four FV PM paralogs in
List of abbreviations
ACTs | artemisinin‐based combination therapies |
ALLN | N-acetyl-Leu-Leu-norleucinal |
AN | artemisinin |
BFA | brefeldin A |
Chr. | chromosome |
CQ | chloroquine |
(k)Da | (kilo‐)dalton |
DDT | dichloro‐diphenyltrichloroethane |
E. coli | Escherichia coli |
E‐64 | L‐3‐carboxy‐2,3‐trans‐epoxypropionyl‐leucylamido(4‐guanidino)butane |
EC50 | half maximal effective concentration |
ECM | experimental cerebral malaria |
EM | electron microscopy |
ER | endoplasmic reticulum |
FP | falcipain |
FV | food vacuole |
GFP | green fluorescence protein |
HAP | Histo‐Aspartic Proteinase |
Hb | hemoglobin |
hBACE‐1 | human β‐secretase 1 |
hcatD | human cathepsin D |
HIV‐1 | human immunodeficiency virus type 1 |
IC50 | half maximal inhibitory concentration |
i.p. | intraperitoneally |
kb | kilo‐base |
kcat | turnover number |
kcat/Km | specificity constant |
Ki | dissociation/inhibition constant |
μM | micromolar |
mM | millimolar |
MS | mass spectrometry |
MW | molecular weight |
NE | nuclear envelope |
nL | norleucine |
nM | nanomolar |
P. | Plasmodium |
Pb | Plasmodium berghei |
PEXEL | Plasmodium export element |
Pf | Plasmodium falciparum |
PfEMP3 | P. falciparum erythrocyte membrane protein 3 |
Pg | Plasmodium gallinaceum |
pH | negative log of the hydrogen ion concentration |
pI | isoelectric point |
PIs | proteinase inhibitors |
PM | plasmepsin |
Pm | Plasmodium malariae |
PMSF | phenylmethylsulfonyl fluoride |
Po | Plasmodium ovale |
PPM | parasite plasma membrane |
PV | parasitophorous vacuole |
Pv | Plasmodium vivax |
PVM | parasitophorous vacuolar membrane |
SEC | size exclusion chromatography |
spp. | species pluralis |
TD50 | median toxic dose |
TV | transport vesicle |
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