Blood Stages Of Plasmodium Falciparum Research Articles

N-aryl-2-aminobenzimidazoles: novel, efficacious, antimalarial lead compounds.

From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.

Aminoazabenzimidazoles, a novel class of orally active antimalarial agents.

Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.

Dual-stage triterpenoids from an African medicinal plant targeting the malaria parasite

Sixteen triterpenoids (1–16), previously isolated from the aerial parts of the African medicinal plant Momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of Plasmodium berghei, measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferase-expressing P. berghei line, PbGFP-Luccon. Toxicity of compounds (1–16) was assessed on the same cell line through the fluorescence measurement of cell confluency. The highest activity was displayed by a derivative bearing two acetyl residues, karavoate B (7), which led to a dose-dependent decrease in the P. berghei infection rate, exhibiting a very significant activity at the lowest concentration employed (1μM) and no toxicity towards the Huh-7 cells. It is noteworthy that, in previous studies, this compound was found to be a strong inhibitor of blood-stages of Plasmodium falciparum, thus displaying a dual-stage antimalarial activity.

Deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.

The discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting EC50 values in the low nanomolar range against asexual blood stages of Plasmodium falciparum in human red blood cells, and Plasmodium berghei liver schizonts, with negligible HepG2 cytotoxicity. Their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. The consensus prediction method suggested a functional resemblance between ligand binding sites in non-homologous target proteins, linking the observed parasite elimination to IspD, an enzyme from the non-mevalonate pathway of isoprenoid biosynthesis, and multi-kinase inhibition. Further computational analysis suggested essential P. falciparum kinases as likely targets of our lead compound. The results obtained validate our methodology for ligand- and structure-based target prediction, expand the bioinformatics toolbox for proteome mining, and provide unique access to deciphering polypharmacological effects of bioactive chemical agents.

Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum.

BackgroundIn view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty.MethodsThe selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as ‘signposts’ in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay.ResultsThis screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series.ConclusionA selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochemical filters, were key to the process. This led to the selection of 15 chemical series from which ten confirmed their activity when newly synthesized sample were tested.

Anti-sporozoite antibodies as alternative markers for malaria transmission intensity estimation

BackgroundReported malaria cases continue to decline globally, and this has been attributed to strategic implementation of multiple malaria control tools. Gains made would however need to be sustained through continuous monitoring to ensure malaria elimination and eradication. Entomological inoculation rate (EIR) is currently the standard tool for transmission monitoring but this is not sensitive enough, especially in areas of very low transmission. Transmission estimation models based on seroconversion rates (λ) of antibodies to Plasmodium falciparum blood stage antigens are gaining relevance. Estimates of λ, which is the measure of transmission intensity, correlate with EIR but are limited by long-term persistence of antibodies to blood stage antigens. Seroprevalence of antibodies to sporozoite antigens may be better alternatives since these antigens usually have shorter immune exposure times. The aim of this study was to develop transmission estimation models based on the seroprevalence of antibodies to two P. falciparum sporozoite antigens (CSP, CelTOS) and compare with models based on the classical blood stage antigen AMA1.MethodsAntibody levels in archived plasma from three cross-sectional surveys conducted in 2009 in a low transmission area of Southern Ghana were assessed by indirect ELISA. Seroprevalence of antibodies against CSP, CelTOS and AMA1 were fitted to reversible catalytic models to estimate λ and corresponding seroreversion rates (ρ) for each antibody.ResultsOf the three models developed, the anti-CSP model predicted a 13-fold decrease in λ four years prior to the time of sampling (2009). Anti-AMA1 antibodies formed at a four-fold greater rate compared to that of anti-CelTOS antibodies, and anti-CSP antibodies during the period of decreased λ. In contrast, anti-AMA1 antibodies decayed at a five-fold slower rate relative to that of anti-CSP antibodies while anti-AMA1 and anti-CelTOS antibody decay rates were not significantly different. Anti-CSP antibodies were relatively short-lived as they formed at an 11.6-fold slower rate relative to their decay during the period of decreased λ.ConclusionsThese features of anti-CSP antibodies can be exploited for the development of models for predicting seasonal, short-term changes in transmission intensity in malaria-endemic areas, especially as the elimination phase of malaria control is approached.

Design, synthesis and biological evaluation of 3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propionic acid hydrazones as antiprotozoal agents

N-Acylhydrazones derived from 7-chloro-4-piperazin-1-yl-quinoline were synthesized and biologically evaluated for blood-stage of Plasmodium falciparum and Entamoeba histolytica trophozoites. N-Acylhydrazone F12 was found to inhibit the P. falciparum growth as well as its life cycle with good selectivity, which was achieved by inhibiting hematin formation. Compound F24 showed better IC50 value than the amoebicidal drug metronidazole.

A search for antiplasmodial metabolites among fungal endophytes of terrestrial and marine plants of southern India.

Eighty four different fungal endophytes isolated from sea grasses (5), marine algae (36) and leaves or barks of forest trees (43) were grown in vitro and the secondary metabolites secreted by them were harvested by immobilizing them on XAD beads. These metabolites were eluted with methanol and screened using SYBR Green I assay for their antiplasmodial activity against blood stage Plasmodium falciparum in human red blood cell culture. Our results revealed that fungal endophytes belonging to diverse genera elaborate antiplasmodial metabolites. A Fusarium sp. (580, IC50: 1.94 μg ml(-1)) endophytic in a marine alga and a Nigrospora sp. (151, IC50: 2.88 μg ml(-1)) endophytic in a tree species were subjected to antiplasmodial activity-guided reversed phase high performance liquid chromatography separation. Purification led to potentiation as reflected in IC50 values of 0.12 μg ml(-1) and 0.15 μg ml(-1) for two of the fractions obtained from 580. Our study adds further credence to the notion that fungal endophytes are a potential storehouse for a variety of novel secondary metabolites vested with different bioactivities including some that can stall the growth of the malaria parasite.

Fungal Endosymbionts of Macroalgae: Need for Enquiries into Diversity and Technological Potential

Recent studies reveal that ascomycete fungi establish an endosymbiotic association with marine algae [1-4]. Akin to the endophytes of terrestrial plants in causing disease-free infections in their hosts, these fungi need to be studied with the same zeal as endophytes as they are a promising source of novel bioactive metabolites. The Fungal Endosymbionts of Macroalage (FEM) elaborate molecules exhibiting antitumour, antioxidant, anticancer, antimicrobial, antifungal, cytotoxic and other bioactivities [5-7]. An Aspergillus sp. harboured by a marine alga elaborates antibiotics effective against methicillin resistant bacteria [8]; FEM isolated from macroalgae of North Atlantic produce antibacterial and larvicidal metabolites [7]. A Fusarium endosymbiont of a marine alga off the coast of southern India formed antimalarial metabolites showing activity against blood stage Plasmodium falciparum [9]. The synthetic ability of FEM is further substantiated by Flewelling et al. [10] who showed that a Penicillium endosymbiont of Fucus spiralis produced epiepoformin, phlyllostine, patulin and cladosporin-a metabolite that has not been previously reported as a product of this genus. Although these few studies identify FEM as a promising source of novel metabolites of pharmaceutical and agricultural importance, a number of challenges confront us before their potential could be fully realized. We identify some roadblocks which need to be addressed.

Immuno-EM Analysis of PF13_0191-GFP Expressing Parasites

This protocol was used to prepare pre-embedding samples of Plasmodium falciparum blood stage parasites that overexpressed the parasite protein PF13_0191 tagged with GFP. Using GFP-specific antibodies and Protein A-Gold the localisation of the overexpressed protein in the infected host cell was determined using standard transmission electron microscopy (EM). Pre-embedding EM is a common method where the antibodies are introduced before embedding and sectioning. This method avoids the problem that antigens are often difficult to detect on EM-sections after embedding. In the method described here antigens in the parasite-infected host cell are detected. Entry of the antibody is made possible through permeabilisation of the host cell with tetanolysin. In principle this method could also be used to detect antigens within the parasite if the sample is appropriately fixed and permeabilised before addition of the relevant antibody. While access of the antibody will avoid the detection problems often seen with post-embedding methods, this procedure will produce comparably poorer morphology.

Preparation of Parasite Protein Extracts and Western Blot Analysis

In order to prepare protein extracts of Plasmodium falciparum blood stages for western blot analysis, infected red blood cells (iRBC) need to be separated from uninfected red blood cells (uRBC) which make up the bulk of the parasite culture. Depending on the localisation of the parasite protein of interest, different methods are available to achieve this. If the protein is present within the parasite or is attached to a cellular structure of the iRBC cell, saponin can be used. This reagent lyses the membranes of infected and uninfected erythrocytes, the Maurer&#180;s clefts (vesicular structures in the iRBC) and the parasitophorous vacuole membrane containing the parasite but leaves the parasite plasma membrane intact, providing a convenient procedure to isolate intact parasites without uRBCs. However, this method has the disadvantage that the host cell cytosol and the parasitophorous vacuole (PV) content of iRBCs are lost. If this has to be avoided, it is possible to use a Percoll gradient to separate intact iRBCs from uRBCs. Sequential treatment with Tetanolysin and saponin can then be used to selectively release the iRBC cytosol and the PV content from the parasite. These selective lysis methods are also suitable to determine the subcellular localisation of a protein of interest.

Human erythrocyte glycophorin C as the receptor for EBA-140 Plasmodium falciparum merozoite ligand

Erythrocyte invasion by the blood-stage Plasmodium falciparum parasites is a multistep process involving specific interactions between parasites and red blood cells. Several proteins are involved in this process, including EBL ligands. The structure of the EBA-140 ligand, a member of the EBL protein family, provides a full description of its molecular interactions with the erythrocyte receptor. The crystal structure of the EBA-140 Region II in a complex with sialolactose revealed that the binding region is monomeric. Two glycan binding pockets, one in each F1 or F2 domain, were identified. Stark differences in the receptor binding for the F1 and F2 domains suggests that each domain performs a distinct function. Although both domains are required for effective glycan binding, it seems that the interaction may be mediated solely by the F1 domain. The structure of the binding region and the interaction with glycan are unique to the EBA-140 ligand and not shared by other EBL ligands. The EBA-140 ligand binds specifically to human erythrocytes through the membrane sialoglycoprotein glycophorin C. The receptor site for the EBA-140 ligand was suggested to be a cluster of N-and O-linked sialylated glycans on the GPC molecule, whose conformation is dependent on the polypeptide chain region composed of amino acid residues 36-63. Precise definition of the binding site for the EBA-140 ligand on glycophorin C may be important with respect to human erythrocyte invasion inhibition strategies based on a receptor.

Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum

BackgroundRecent whole cell in vitro screening campaigns identified thousands of compounds that are active against asexual blood stages of Plasmodium falciparum at submicromolar concentrations. These hits have been made available to the public, providing many novel chemical starting points for anti-malarial drug discovery programmes. Knowing which of these hits are fast-acting compounds is of great interest. Firstly, a fast action will ensure rapid relief of symptoms for the patient. Secondly, by rapidly reducing the parasitaemia, this could minimize the occurrence of mutations leading to new drug resistance mechanisms.An in vitro assay that provides information about the speed of action of test compounds has been developed by researchers at GlaxoSmithKline (GSK) in Spain. This assay also provides an in vitro measure for the ratio between parasitaemia at the onset of drug treatment and after one intra-erythrocytic cycle (parasite reduction ratio, PRR). Both parameters are needed to determine in vitro killing rates of anti-malarial compounds. A drawback of the killing rate assay is that it takes a month to obtain first results.MethodsThe approach described in the present study is focused only on the speed of action of anti-malarials. This has the advantage that initial results can be achieved within 4–7 working days, which helps to distinguish between fast and slow-acting compounds relatively quickly. It is expected that this new assay can be used as a filter in the early drug discovery phase, which will reduce the number of compounds progressing to secondary, more time-consuming assays like the killing rate assay.ResultsThe speed of action of a selection of seven anti-malarial compounds was measured with two independent experimental procedures using modifications of the standard [3H]hypoxanthine incorporation assay. Depending on the outcome of both assays, the tested compounds were classified as either fast or non-fast-acting.ConclusionThe results obtained for the anti-malarials chloroquine, artesunate, atovaquone, and pyrimethamine are consistent with previous observations, suggesting the methodology is a valid way to rapidly identify fast-acting anti-malarial compounds. Another advantage of the approach is its ability to discriminate between static or cidal compound effects.

CRIMALDDI: platform technologies and novel anti-malarial drug targets

The Coordination, Rationalization, and Integration of antiMALarial drug Discovery & Development Initiatives (CRIMALDDI) Consortium, funded by the EU Framework Seven Programme, has attempted, through a series of interactive and facilitated workshops, to develop priorities for research to expedite the discovery of new anti-malarials. This paper outlines the recommendations for the development of enabling technologies and the identification of novel targets.Screening systems must be robust, validated, reproducible, and represent human malaria. They also need to be cost-effective. While such systems exist to screen for activity against blood stage Plasmodium falciparum, they are lacking for other Plasmodium spp. and other stages of the parasite’s life cycle. Priority needs to be given to developing high-throughput screens that can identify activity against the liver and sexual stages. This in turn requires other enabling technologies to be developed to allow the study of these stages and to allow for the culture of liver cells and the parasite at all stages of its life cycle.As these enabling technologies become available, they will allow novel drug targets to be studied. Currently anti-malarials are mostly targeting the asexual blood stage of the parasite’s life cycle. There are many other attractive targets that need to be investigated. The liver stages and the sexual stages will become more important as malaria control moves towards malaria elimination. Sexual development is a process offering multiple targets, even though the mechanisms of differentiation are still not fully understood. However, designing a drug whose effect is not curative but would be used in asymptomatic patients is difficult given current safety thresholds. Compounds active against the liver schizont would have a prophylactic effect and Plasmodium vivax elimination requires effectors against the dormant liver hypnozoites. It may be that drugs to be used in elimination campaigns will also need to have utility in the control phase. Compounds with activity against blood stages need to be screened for activity against other stages.Natural products should also be a valuable source of new compounds. They often occupy non-Lipinski chemical space and so may reveal valuable new chemotypes.

Reliability of School Surveys in Estimating Geographic Variation in Malaria Transmission in the Western Kenyan Highlands

BackgroundSchool surveys provide an operational approach to assess malaria transmission through parasite prevalence. There is limited evidence on the comparability of prevalence estimates obtained from school and community surveys carried out at the same locality.MethodsConcurrent school and community cross-sectional surveys were conducted in 46 school/community clusters in the western Kenyan highlands and households of school children were geolocated. Malaria was assessed by rapid diagnostic test (RDT) and combined seroprevalence of antibodies to bloodstage Plasmodium falciparum antigens.ResultsRDT prevalence in school and community populations was 25.7% (95% CI: 24.4-26.8) and 15.5% (95% CI: 14.4-16.7), respectively. Seroprevalence in the school and community populations was 51.9% (95% CI: 50.5-53.3) and 51.5% (95% CI: 49.5-52.9), respectively. RDT prevalence in schools could differentiate between low (<7%, 95% CI: 0-19%) and high (>39%, 95% CI: 25-49%) transmission areas in the community and, after a simple adjustment, were concordant with the community estimates.ConclusionsEstimates of malaria prevalence from school surveys were consistently higher than those from community surveys and were strongly correlated. School-based estimates can be used as a reliable indicator of malaria transmission intensity in the wider community and may provide a basis for identifying priority areas for malaria control.

Improved Efficacy of Fosmidomycin against Plasmodium and Mycobacterium Species by Combination with the Cell-Penetrating Peptide Octaarginine

Cellular drug delivery can improve efficacy and render intracellular pathogens susceptible to compounds that cannot permeate cells. The transport of physiologically active compounds across membranes into target cells can be facilitated by cell-penetrating peptides (CPPs), such as oligoarginines. Here, we investigated whether intracellular delivery of the drug fosmidomycin can be improved by combination with the CPP octaarginine. Fosmidomycin is an antibiotic that inhibits the second reaction in the nonmevalonate pathway of isoprenoid biosynthesis, an essential pathway for many obligate intracellular pathogens, including mycobacteria and apicomplexan parasites. We observed a strict correlation between octaarginine host cell permeability and its ability to improve the efficacy of fosmidomycin. Plasmodium berghei liver-stage parasites were only partially susceptible to an octaarginine-fosmidomycin complex. Similarly, Toxoplasma gondii was only susceptible during the brief extracellular stages. In marked contrast, a salt complex of octaarginine and fosmidomycin greatly enhanced efficacy against blood-stage Plasmodium falciparum. This complex and a covalently linked conjugate of octaarginine and fosmidomycin also reverted resistance of Mycobacteria to fosmidomycin. These findings provide chemical genetic evidence for vital roles of the nonmevalonate pathway of isoprenoid biosynthesis in a number of medically relevant pathogens. Our results warrant further investigation of octaarginine as a delivery vehicle and alternative fosmidomycin formulations for malaria and tuberculosis drug development.

Structural modification of pantothenamides counteracts degradation by pantetheinase and improves antiplasmodial activity.

Pantothenamides are secondary or tertiary amides of pantothenic acid, the vitamin precursor of the essential cofactor and universal acyl carrier coenzyme A. A recent study has demonstrated that pantothenamides inhibit the growth of blood-stage Plasmodium falciparum with submicromolar potency by exerting an effect on pantothenic acid utilization, but only when the pantetheinase present in the growth medium has been inactivated. Here, we demonstrate that small modifications of the pantothenamide core structure are sufficient to counteract pantetheinase-mediated degradation and that the resulting pantothenamide analogues still inhibit the in vitro proliferation of P. falciparum by targeting a pantothenic acid-dependent process (or processes). Finally, we investigated the toxicity of the most potent analogues to human cells and show that the selectivity ratio exceeds 100 in one case. Taken together, these results provide further support for pantothenic acid utilization being a viable target for antimalarial drug discovery.

Mitochondrial metabolism of sexual and asexual blood stages of the malaria parasite Plasmodium falciparum

BackgroundThe carbon metabolism of the blood stages of Plasmodium falciparum, comprising rapidly dividing asexual stages and non-dividing gametocytes, is thought to be highly streamlined, with glycolysis providing most of the cellular ATP. However, these parasitic stages express all the enzymes needed for a canonical mitochondrial tricarboxylic acid (TCA) cycle, and it was recently proposed that they may catabolize glutamine via an atypical branched TCA cycle. Whether these stages catabolize glucose in the TCA cycle and what is the functional significance of mitochondrial metabolism remains unresolved.ResultsWe reassessed the central carbon metabolism of P. falciparum asexual and sexual blood stages, by metabolically labeling each stage with 13C-glucose and 13C-glutamine, and analyzing isotopic enrichment in key pathways using mass spectrometry. In contrast to previous findings, we found that carbon skeletons derived from both glucose and glutamine are catabolized in a canonical oxidative TCA cycle in both the asexual and sexual blood stages. Flux of glucose carbon skeletons into the TCA cycle is low in the asexual blood stages, with glutamine providing most of the carbon skeletons, but increases dramatically in the gametocyte stages. Increased glucose catabolism in the gametocyte TCA cycle was associated with increased glucose uptake, suggesting that the energy requirements of this stage are high. Significantly, whereas chemical inhibition of the TCA cycle had little effect on the growth or viability of asexual stages, inhibition of the gametocyte TCA cycle led to arrested development and death.ConclusionsOur metabolomics approach has allowed us to revise current models of P. falciparum carbon metabolism. In particular, we found that both asexual and sexual blood stages utilize a conventional TCA cycle to catabolize glucose and glutamine. Gametocyte differentiation is associated with a programmed remodeling of central carbon metabolism that may be required for parasite survival either before or after uptake by the mosquito vector. The increased sensitivity of gametocyte stages to TCA-cycle inhibitors provides a potential target for transmission-blocking drugs.

Progressing the global antimalarial portfolio: finding drugs which target multiple Plasmodium life stages

The number of novel antimalarial candidates entering preclinical development has seen an increase over the last several years. Most of these drug candidates were originally identified as hits coming from screening large chemical libraries specifically targeting the asexual blood stages of Plasmodium falciparum. Indeed, a large proportion of the current antimalarial arsenal has mainly targeted the asexual blood stage which is responsible for clinical symptoms of the disease. However, as part of the eradication agenda and to address resistance, any next-generation antimalarial should have additional activity on at least one other parasite life stage, i.e. gametocytocidal and/or tissue schizonticidal activity. We have applied this approach by screening compounds with intrinsic activity on asexual blood stages in assays against sexual and liver stages and identified two new antimalarial chemotypes with activity on multiple parasite life stages. This strategy can be expanded to identify other chemical classes of molecules with similar activity profiles for the next generation antimalarials. The following review summarizes the discovery of the spiroindolones and imidazolopiperazine classes of antimalarials developed by the NGBS consortium (Novartis Institute for Tropical Diseases, Genomic Institute of the Novartis Research Foundation, Biomedical Primate Research Center, and the Swiss Tropical and Public Health Institute) currently in clinical trials.

Association of HLA‐G 3′ untranslated region polymorphisms with antibody response against Plasmodium falciparum antigens: preliminary results

Host and Plasmodium interactions result in highly variable clinical phenotypes, partly explained by the nature and level of anti-malarial antibody response. Human leukocyte antigen (HLA)-G can create a tolerogenic environment, allowing parasites to escape from anti-malarial immunity. We performed a family-based association study encompassing 483 Sereer individuals (261 children and their parents), and reported two independent signals at the HLA-G 3' untranslated region associated with antibody response to specific Plasmodium falciparum blood stage antigens, previously associated with malaria protection: (i) +3010G together with +3142C with total IgG and IgG1 against GLURP and (ii) +3196G with IgG3 against MSP2. While these results require further investigation, they suggest for the first time a role of HLA-G in the regulation of humoral immune response in malaria.