Antimalarial Research Articles

Challenges of Severe Malaria Management in Patient Returning from Jayapura, Indonesia Presented with Severe Anemia: A Case Report

We report a 55-year-old woman who presented to the hospital with intermittent fever for a month. The patient had a history of living in a malaria endemic area (Jayapura, Papua Province, Indonesia) for approximately 15 years. The hemoglobin level was very low (4.2 mg/dL). Furthermore, we conducted a follow-up supporting examination, Malaria Rapid Diagnostic Test (RDT), the result was positive for malaria tropica (Plasmodium falciparum). Blood smear test was also carried out to confirm the diagnosis, the result was that immature trophozoites (ring shape) were found. Thus, the patient was diagnosed with severe malaria tropica with clinical manifestations indicative of severe anemia. The patient was treated for 3 days with anti-malarial drugs and supportive drugs according to the symptoms in the hospital and was advised to follow up 7 days later. This case report describe the challenges of severe malaria management in patient returning from Jayapura with severe anemia.

Cryptolepine: A naturally derived alkaloid inhibits breast cancer progression by blocking cell cycle progression and inducing apoptosis.

e13151 Background: Triple Negative Breast cancer is an aggressive breast cancer subtype. TNBC has a more aggressive clinical course, an earlier age of beginning, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate when compared to hormone receptor-positive or HER2-positive illness. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments, however, remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60–88% of TNBC, translating p53 into the clinical situation is particularly important in TNBC. Given the scope that some natural drugs can be used as specifically targeting prospective therapeutic in TNBC and to sensitize this aggressive malignancy while reducing side effects. In this study, we screened and evaluated the therapeutic potential of CRP in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic in TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported. Methods: MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate cryptolepine’s effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay. Results: In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism that cryptolepine can induce intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability and also inducing its own transcriptional activation to synthesize new P53 protein and hence activating its tumor suppressing potential significantly. Conclusions: Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability.

Antimalarial Studies and Phytochemical Profiling of Laportea aestuans (L.) Chew Extractives

Background and objectives This study validated the antimalarial efficacy of Laportea aestuans extract using chemosuppressive and curative models, identified its most active fraction, and performed chemical profiling of the active fraction. Methodology The aerial part of L. aestuans (LA) was extracted with 80% methanol and assayed for its chemosuppressive and curative antimalarial activities through the oral administration of the extract (100, 200, 400 and 800 mg/kg) to groups consisting of five mice each. The extract was thereafter suspended in water and partitioned with dichloromethane to afford the dichloromethane (DLA) and aqueous (ALA) fractions. The fractions (10, 20, 40, and 80 mg/kg) were thereafter tested for their antimalarial activity followed by GC-MS analysis of the most active fraction. Results The toxicity level was found to be above 2000 mg/kg. The activity recorded for the four-day chemosuppressive antimalarial tests showed a dose-dependent activity up to 400 mg/kg. The activity was significantly lower than that of chloroquine. The antimalarial activity of the extract at the lowest dose of 100 mg/kg was 42%. In the curative test, the extract of LA gave a dose-dependent activity that was significantly higher than the negative control. The DLA and ALA fractions gave a comparable curative activity across all doses. At 10 mg/kg, ALA and DLA gave percentage clearance of 81.25 ± 1.84 and 87.45 ± 1.35, respectively, which were significantly higher than that of the negative control (0.00 ± 0.00) and significantly lower than that of the positive control (94.93 ± 0.26). The chemical profiling revealed the presence of non-polar and medium-polar constituents in the dichloromethane fraction. Conclusion The good antimalarial activity elicited by LA extractives supports its usage in ethnomedicine as an antimalarial agent.

Exploration and Characterization of Johar (Cassia siamea) Accession as a Source of Raw Material for Antimalaria Drug

Abstract Johar is a medicinal plant belonging to the Fabaceae family, often planted as a roadside shade. Empirically, johar leaf is used for traditional medicine, including malaria, itching, scabies, diabetes, fever, wounds, and tonic. The active compound responsible for the antimalarial activity, Casiarine A, has been successfully isolated and identified from the johar leaf. The availability of johar plants with a high content of Casiarine A as the active compound is very necessary. For this reason, exploration and characterization of johar were carried out to provide superior accessions with high biomass production and bioactive compound content. The research was conducted in an exploratory accession of the plants from certain Central and East Java areas. The sample plants were morphologically characterized, and productivity tests were investigated, including the simplicia dry yield, total extract content, and phytochemical profile. The results showed that 13 johar accessions were obtained from 13 growing regions with similar morphological characters. The main differences observed were in the size, color, and shape of the leaves. The growth location affects dry yield, total extract content, and phytochemical profile. Based on the measured parameters, Johar accessions were grouped into lowland, midland, and highland clusters according to their growth locations.

Biogenesis of cytochromes c and c 1 in the electron transport chain of malaria parasites.

Plasmodium malaria parasites retain an essential mitochondrional electron transport chain (ETC) that is critical for growth within humans and mosquitoes and a key antimalarial drug target. ETC function requires cytochromes c and c 1 that are unusual among heme proteins due to their covalent binding to heme via conserved CXXCH sequence motifs. Heme attachment to these proteins in most eukaryotes requires the mitochondrial enzyme holocytochrome c synthase (HCCS) that binds heme and the apo cytochrome to facilitate biogenesis of the mature cytochrome c or c 1. Although humans encode a single bifunctional HCCS that attaches heme to both proteins, Plasmodium parasites are like yeast and encode two separate HCCS homologs thought to be specific for heme attachment to cyt c (HCCS) or cyt c 1 (HCC1S). To test the function and specificity of P. falciparum HCCS and HCC1S, we used CRISPR/Cas9 to tag both genes for conditional expression. HCC1S knockdown selectively impaired cyt c 1 biogenesis and caused lethal ETC dysfunction that was not reversed by over-expression of HCCS. Knockdown of HCCS caused a more modest growth defect but strongly sensitized parasites to mitochondrial depolarization by proguanil, revealing key defects in ETC function. These results and prior heterologous studies in E. coli of cyt c hemylation by P. falciparum HCCS and HCC1S strongly suggest that both homologs are essential for mitochondrial ETC function and have distinct specificities for biogenesis of cyt c and c 1, respectively, in parasites. This study lays a foundation to develop novel strategies to selectively block ETC function in malaria parasites.

Development of Phytoconstituents from Spathodea campanulata Flowers as Potential Antimalarial Agents

Background: Considering the majority of pharmaceutical firms focus on using herbal remedies as an alternative source of essential components, herbal remedies are extremely significant to pharmacological researchers. Spathodea campanulata is one of the members of the Bignoniaceae family. It is popular for its curative properties Aim: This research aimed to assess the possibility of bioactive elements and antioxidant impacts of the methanol fraction of Spathodea campanulata flowers. Objectives: The objective of this research was to assess the achievable bioactive elements and antioxidant impacts of the methanol fraction of Spathodea campanulata flowers. Methods: GC-MS was adopted to identify the phytoconstituents present in the extract. In the present study, we utilized computational modelling with the Schrödinger Maestro 11.2 edition to make benefit of interactions among 42 bio-active components and anti-malarial targets (1LDG and 2ANL). Results: In the methanol extract of the Spathodea campanulata flowers, phytochemical research revealed the presence of terpenoids, glycosides, carbohydrates, steroids, and flavonoids. Forty-two phytoconstituents, notably methyl-beta-d-galactopyranoside, 4-hydroxybenzoic acid, and 1,2- ethanediol monobenzoate, were determined through GC-MS analysis. Docking analysis of 42 bioactive compounds demonstrated that 1,2-ethanediol mono benzoate, 4-hydroxy benzoic acid, and methyl.beta.-d-galactopyranoside had higher G-Scores with 1LDG and 2ANL. Conclusion: In this work, multiple phytoconstituents discovered in a methanol extract of the S. campanulata flower were determined. As a result of this research, four phytoconstituents from the flower extracts may be created as an exciting new therapy for malaria.

Efficacy of Albizia malacophylla (A.Rich.) Walp. (Leguminosae) methanol (80%) leaf extract and solvent fractions against Plasmodium berghei-induced malaria in mice model

Ethnopharmacological relevanceNovel drugs are needed to address the issue of malarial infection resistance; natural items can be a different source of these medications. Albizia malacophylla (A. Rich.) Walp. (Leguminosae) is listed as one of the antimalarial medicinal plants in Ethiopian folk medicine. However, there are no reports regarding the biological activity or phytochemistry of the plant. Aim of the studyThus, this study aimed to evaluate the A. malacophylla crude extract and solvent fractions' in vivo antimalarial activity utilizing 4-day suppressive, preventative, and curative tests in mice infected with P. berghei. Materials and methodsThe parasite Plasmodium berghei, which causes rodent malaria, was used to infect healthy male Swiss Albino mice, weighing 23–28 g and aged 6–8 weeks. Solvent fractions such as methanol, water, and chloroform were given in addition to an 80% methanolic extract at 100, 200, and 400 mg/kg doses. A Conventional test such as parasitemia, survival time, body weight, temperature, and packed cell capacity were employed to ascertain factors such as the suppressive, curative, and preventive tests. ResultsEvery test substance dramatically reduced the number of parasites in every experiment. Crude extract (with the highest percentage suppression of 67.78%) performs better antimalarial effect than the methanol fraction, which is the most efficient solvent fraction with a percentage suppression of 55.74%. With a suppression value of 64.83% parasitemia level, the therapeutic effects of 80% methanolic crude extract were greater than its curative and preventative effects in a four-day suppressive test. The survival period (17 days) was longer with the hydroalcoholic crude extract dose of 400 mg/kg than with other doses of the materials under investigation. ConclusionsThe results of this investigation validate the antimalarial characteristics of A. malacophylla leaf extract. The crude extract prevented weight loss, a decline in temperature, and a reduction in PCV. The results demonstrate that the plant has a promising antimalarial effect against P. berghei, hence supporting the traditional use of the plant. Therefore, it could serve as a foundation for the development of new antimalarial drugs.

To quest new targets of Plasmodium parasite and their potential inhibitors to combat antimalarial drug resistance.

Malaria remains a global health challenge with significant mortality and morbidity annually, with resistant parasite strains complicating treatment efforts. There is an acute need for novel antimalarial drugs that can put a stop to the future public health crisis caused by the multi-drug resistance strains of the Plasmodium parasite. However, the discovery of these new components is very challenging in the context of the generation of multi-drug resistance properties of malaria. The novel drugs also need to have several properties involving enhanced therapeutic prospects, successful treatment capabilities, and novel mechanisms of action that will forestall the resistance. To successfully achieve this aim researchers are trying to focus on exploring promising malaria targets. Various approaches have been made for the development of drugs for malaria including the remodelling of existing drugs and the development of novel inhibitors which acts on new targets. Advancement in the study provides more information on the biology of parasites and the new targets which help in the development of novel drugs. The present review focuses on the study of novel targets of malaria parasites and subsequent inhibitors of those particular targets. Some of these targets include malarial protease, various transporter proteins, enzymes involved in the synthesis of DNA, and nucleic acids like dihydroorotate dehydrogenase, dihydrofolate reductase, apicoplast and dihydropteroate synthase. Other potential targets are also included in this review such as isoprenoid biosynthesis, farnesyl transferase of parasite, P. falciparum translational elongation factor 2, and phosphatidyl inositol 4 kinase. These promising targets have also been summed up along with their corresponding inhibitors for combating multi-drug resistance malaria.

Role of Rabenosyn-5 and Rab5b in host cell cytosol uptake reveals conservation of endosomal transport in malaria parasites.

Vesicular trafficking, including secretion and endocytosis, plays fundamental roles in the unique biology of Plasmodium falciparum blood-stage parasites. Endocytosis of host cell cytosol (HCC) provides nutrients and room for parasite growth and is critical for the action of antimalarial drugs and parasite drug resistance. Previous work showed that PfVPS45 functions in endosomal transport of HCC to the parasite's food vacuole, raising the possibility that malaria parasites possess a canonical endolysosomal system. However, the seeming absence of VPS45-typical functional interactors such as rabenosyn 5 (Rbsn5) and the repurposing of Rab5 isoforms and other endolysosomal proteins for secretion in apicomplexans question this idea. Here, we identified a parasite Rbsn5-like protein and show that it functions with VPS45 in the endosomal transport of HCC. We also show that PfRab5b but not PfRab5a is involved in the same process. Inactivation of PfRbsn5L resulted in PI3P and PfRab5b decorated HCC-filled vesicles, typical for endosomal compartments. Overall, this indicates that despite the low sequence conservation of PfRbsn5L and the unusual N-terminal modification of PfRab5b, principles of endosomal transport in malaria parasite are similar to that of model organisms. Using a conditional double protein inactivation system, we further provide evidence that the PfKelch13 compartment, an unusual apicomplexa-specific endocytosis structure at the parasite plasma membrane, is connected upstream of the Rbsn5L/VPS45/Rab5b-dependent endosomal route. Altogether, this work indicates that HCC uptake consists of a highly parasite-specific part that feeds endocytosed material into an endosomal system containing more canonical elements, leading to the delivery of HCC to the food vacuole.

Lacrimal gland Alterations and the Effect of artesunate on experimental induced diabetes rat models and related mechanisms

Diabetic patients are at high risk of developing lacrimal gland dysfunction, and the antimalarial drug artesunate (ART) was recently used to induce experimental-induced diabetes mellitus. This study’s objective is to investigate the lacrimal gland alteration and the effect of ART on experimentally induced diabetes rat models and its related mechanisms. Forty rats were divided into five groups (8 rats/group): healthy control group (HC), diabetic group (DM), 50 mg/kg ART intervention diabetic group [DM + ART (50 mg/kg)], 100 mg/kg ART intervention diabetic group [DM + ART (100 mg/kg)] and 6 U/kg Insulin intervention diabetic group (DM + INS). The morphology of the eyeball and lacrimal gland tissues was determined using hematoxylin and eosin staining. In addition, external lacrimal glands were harvested for electronic microscopic examination, NFκB1, and TNF-α protein expression evaluation by immunohistochemistry and mRNA expression analysis by RT-PCR. Histopathological and ultrastructural changes suggest ART intervention has an improved structural effect. Protein expression of NFκB1 in the DM + ART (100 mg/kg) group was decreased. TNF-α significantly decreased in the DM + ART (50 mg/kg) and insulin groups. We concluded that ART improves structural changes in a lacrimal gland in diabetic rats. The present study provides further evidence of the therapeutic effect of ART on the lacrimal gland of diabetic rats by decreasing the expression of NFκB1 and TNF-α.

Antimalarial Drug Discovery from Natural and Synthetic Sources.

Malaria remains a significant global health threat despite extensive efforts aimed at its eradication. Numerous challenges persist in eliminating the disease, chief among them being the parasite's ability to mutate, resulting in drug resistance. The discovery of antimalarial drugs has relied on both phenotypic and target-based approaches. While phenotypic screening has identified promising candidates, target-based methods offer a more precise approach by leveraging chemically validated targets and computational tools. Analysis of Plasmodium spp. protein structures reveal druggable targets, offering opportunities for in silico screening. Combining compounds from natural and synthetic sources in a target-based approach accelerates the discovery of new antimalarial agents. This review explores previous breakthroughs in antimalarial drug discovery from natural products and synthetic origins, emphasizing their specific target proteins within Plasmodium species.

Malaria prevention practices among patients attending the NTOUM departmental hospital, Northwest Gabon

Introduction: In Gabon, a territory located in Central Africa, prevention is an essential measure in the fight against malaria. The aim of this study was to evaluate, in the Komo-Mondah department, the prophylaxis practices employed by the inhabitants of the commune of Ntoum and the prevalence of anti-malarial drugs prescribed by local doctors. Methods: We carried out a prospective, cross-sectional study over a 3-month period, on patients of both sexes and of all ages who came for consultation to the departmental hospital of Ntoum. Patients who had a prescription for malaria drugs at the end of their medical visit were included in the study. Results: Of the 248 subjects enrolled, children under 5 years of age were the main victims (84%).Indeed, children under 5 were two (2) and three (3) times more likely to test positive to malaria than the age group 16-24 (OR = 2.44 [1.05 - 5.63]; P ˂ 0.05) , 25 and over (OR= 3.10 [1.46 - 6.59]; P ˂ 0.05), respectively. Anti-malaria prophylaxis was practiced by 80% of the study population. Patients who declared sleeping under a bed net appear to be protected compare to those who did not (OR= 0.53 [0.28 - 0.97] ; P ˂ 0.05). Self-medication was recorded in 29% of patients, and the drugs most commonly prescribed by doctors were artemisinin-based combinations, including Artefan (51%), Coartem (30%) and Eurartesim (2%). Conclusion: Although conventional prophylaxis measures (vector control and chemoprevention) are adopted by many Gabonese, careful pharmacological management and the implementation of targeted, long-term prevention-surveillance and health education strategies will enable effective malaria control in this part of Gabon.

Public-private partnerships in health sector innovation: Lessons from around the world

Public-Private Partnerships (PPPs) have emerged as a crucial mechanism for fostering innovation in the health sector globally. This review encapsulates the lessons learned from diverse PPP models worldwide, highlighting their significance and impact. PPPs in healthcare innovation entail collaboration between governmental bodies, private enterprises, and sometimes non-profit organizations to address challenges, such as limited resources, expertise, and infrastructure, while leveraging the strengths of each sector. The success of PPPs relies on effective governance structures, clear objectives, and mutual accountability. One notable example is the United Kingdom's NHS Innovation Accelerator, which partners with industry leaders to fast-track the adoption of innovative healthcare technologies within the National Health Service (NHS). Through this initiative, pioneering solutions, ranging from digital health platforms to medical devices, have been implemented, enhancing patient care and operational efficiency. Similarly, in low-resource settings like sub-Saharan Africa, PPPs have played a pivotal role in improving access to essential healthcare services. Projects such as the Medicines for Malaria Venture (MMV) collaborate with pharmaceutical companies, governments, and research institutions to develop affordable antimalarial drugs tailored to the region's needs. In the realm of medical research and development, partnerships like the Coalition for Epidemic Preparedness Innovations (CEPI) have demonstrated the power of international collaboration in addressing global health threats. CEPI brings together governments, philanthropic organizations, and the private sector to expedite the development of vaccines against emerging infectious diseases, as witnessed during the COVID-19 pandemic. However, challenges persist in PPP implementation, including complex regulatory frameworks, funding uncertainties, and divergent interests among stakeholders. Lessons from successful PPPs underscore the importance of transparent communication, stakeholder engagement, and sustained political commitment. In conclusion, PPPs in the health sector represent a dynamic avenue for catalyzing innovation and driving transformative change. By drawing insights from diverse experiences worldwide, policymakers and practitioners can refine existing frameworks and foster sustainable partnerships to tackle evolving health challenges effectively.

Challenges in the distribution of antimicrobial medications in community dispensaries in Accra, Ghana.

The dispensation of medicines in some low- and middle-income countries is often carried out by private vendors operating under constrained conditions. The aim of this study was to understand the challenges reported by employees of dispensaries, specifically, chemical and herbal shops and pharmacies in Accra, Ghana. Our objectives were twofold: (1) to assess challenges faced by medicine vendors related to dispensing antimicrobials (antibiotic and antimalarial medications), and (2) to identify opportunities for improving their stewardship of antimicrobials. Data were collected in 79 dispensaries throughout Accra, in 2021, using a survey questionnaire. We used open-ended questions, grounded on an adapted socioecological model of public health, to analyze these data and determine challenges faced by respondents. We identified multiple, interlocking challenges faced by medicine vendors. Many of these relate to challenges of antimicrobial stewardship (following evidence-based practices when dispensing medicines). Overall, medicine vendors frequently reported challenges at the Customer and Community levels. These included strained interactions with customers and the prohibitive costs of medications. The consequences of these challenges reverberated and manifested through all levels of the socioecological model of public health (Entity, Customer, Community, Global). The safe and effective distribution of medications was truncated by strained interactions, often related to the cost of medicines and gaps in knowledge. While addressing these challenges requires multifaceted approaches, we identified several areas that, if intervened upon, could unlock the great potential of antimicrobal stewardship. The effective and efficient implementation of key interventions could facilitate efforts spearheaded by medicine vendors and leverage the benefits of their role as health educators and service providers. Addressing barriers faced by medicine vendors would provide an opportunity to significantly improve the provision of medications, and ultimately population health. Such efforts will likely expand access to populations who may otherwise be unable to access medications and treatment in formal institutions of care such as hospitals. Our findings also highlight the broad range of care provided by shopkeepers and vendors at dispensaries. These findings suggest that the meaningful engagement of dispensaries as valued conduits of community health is a promising pathway for interventions aiming to improve antimicrobial stewardship.

A high content imaging assay for identification of specific inhibitors of native Plasmodium liver stage protein synthesis.

Plasmodium parasite resistance to antimalarial drugs is a serious threat to public health in malaria-endemic areas. Compounds that target core cellular processes like translation are highly desirable, as they should be multistage actives, capable of killing parasites in the liver and blood, regardless of molecular target or mechanism. Assays that can identify these compounds are thus needed. Recently, specific quantification of native Plasmodium berghei liver stage protein synthesis as well as that of the hepatoma cells supporting parasite growth, was achieved via automated confocal feedback microscopy of the o-propargyl puromycin (OPP)-labeled nascent proteome, but this imaging modality is limited in throughput. Here, we developed and validated a miniaturized high content imaging (HCI) version of the OPP assay that increases throughput, before deploying this approach to screen the Pathogen Box. We identified only two hits, both of which are parasite-specific quinoline-4-carboxamides, and analogues of the clinical candidate and known inhibitor of blood and liver stage protein synthesis, DDD107498/cabamiquine. We further show that these compounds have strikingly distinct relationships between their antiplasmodial and translation inhibition efficacies. These results demonstrate the utility and reliability of the P. berghei liver stage OPP HCI assay for specific, single-well quantification of Plasmodium and human protein synthesis in the native cellular context, allowing identification of selective Plasmodium translation inhibitors with the highest potential for multistage activity.

From multiplicity of infection to force of infection for sparsely sampled Plasmodium falciparum populations at high transmission.

High multiplicity of infection or MOI, the number of genetically distinct parasite strains co-infecting a single human host, characterizes infectious diseases including falciparum malaria at high transmission. It accompanies high asymptomatic Plasmodium falciparum prevalence despite high exposure, creating a large transmission reservoir challenging intervention. High MOI and asymptomatic prevalence are enabled by immune evasion of the parasite achieved via vast antigenic diversity. Force of infection or FOI, the number of new infections acquired by an individual host over a given time interval, is the dynamic sister quantity of MOI, and a key epidemiological parameter for monitoring the impact of antimalarial interventions and assessing vaccine or drug efficacy in clinical trials. FOI remains difficult, expensive, and labor-intensive to accurately measure, especially in high-transmission regions, whether directly via cohort studies or indirectly via the fitting of epidemiological models to repeated cross-sectional surveys. We propose here the application of queuing theory to obtain FOI on the basis of MOI, in the form of either a two-moment approximation method or Little's law. We illustrate these methods with MOI estimates obtained under sparse sampling schemes with the recently proposed " coding" method, based on sequences of the multigene family encoding for the major variant surface antigen of the blood stage of malaria infection. The methods are evaluated with simulation output from a stochastic agent-based model, and are applied to an interrupted time-series study from Bongo District in northern Ghana before and immediately after a three-round transient indoor residual spraying (IRS) intervention. We incorporate into the sampling of the simulation output, limitations representative of those encountered in the collection of field data, including under-sampling of genes, missing data, and usage of antimalarial drug treatment. We address these limitations in MOI estimates with a Bayesian framework and an imputation bootstrap approach. We demonstrate that both proposed methods give good and consistent FOI estimates across various simulated scenarios. Their application to the field surveys shows a pronounced reduction in annual FOI during intervention, of more than 70%. The proposed approach should be applicable to the many geographical locations where cohort or cross-sectional studies with regular and frequent sampling are lacking but single-time-point surveys under sparse sampling schemes are available, and for MOI estimates obtained in different ways. They should also be relevant to other pathogens of humans, wildlife and livestock whose immune evasion strategies are based on large antigenic variation resulting in high multiplicity of infection.

Biological threats to global malaria elimination I Antimalarial drug resistance

Malaria is an infectious disease that seriously threatens human health. Currently, malaria control mainly depends on antimalarial chemotherapy. However, antimalarial drug resistance is becoming increasingly severe, which poses a great challenge to malaria control, notably treatment of Plasmodium falciparum malaria. To address this challenge, there is a need to facilitate development of novel antimalarial drugs and innovation of treatment strategies, as well as reinforce surveillance and research on antimalarial drug resistance. This article reviews the main categories and use guidelines of current antimalarial agents, summarizes the current status and monitoring methods of antimalarial drug resistance, and proposes the response to antimalarial drug resistance, so as to provide insights into the use of antimalarial drugs and response to antimalarial drug resistance, and contribute to global malaria elimination.

Analysis of the interaction of antimalarial agents with Plasmodium falciparum glutathione reductase through molecular mechanical calculations.

Malaria remains a significant global health challenge with emerging resistance to current treatments. Plasmodium falciparum glutathione reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarials and dual drugs combining aminoquinoline derivatives with GR inhibitors, which reveal promising interactions between PfGR and studied drugs. The naphthoquinone Atovaquone demonstrated particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity, suggesting their efficacy in inhibiting PfGR, where the aliphatic ester bond (linker) is essential for effective binding with the enzyme's active site. Overall, this research provides important insights into the interactions between antimalarial agents and PfGR and encourages further exploration of its role in the mechanisms of action of antimalarials, including dual drugs, to enhance antiparasitic efficacy. The drugs were tested as PfGR potential inhibitors via molecular docking on AutoDock 4, which was performed based on the preoptimized structures in HF/3-21G-PCM level of theory on ORCA 5. Drug-receptor systems with the most promising binding affinities were then studied with a molecular dynamic's simulation on AMBER 16. The molecular dynamics simulations were performed with a 100ns NPT ensemble employing GAFF2 forcefield in the temperature of 310K, integration time step of 2fs, and non-bond cutoff distance of 6.0Å.

Fragment-based virtual screening identifies novel leads against Plasmepsin IX (PlmIX) of Plasmodium falciparum: Homology modeling, molecular docking, and simulation approaches

Despite continuous efforts to develop safer and efficient medications, malaria remains a major threat posing great challenges for new drug discovery. The emerging drug resistance, increased toxicities, and impoverished pharmacokinetic profiles exhibited by conventional drugs have hindered the search for new entities. Plasmepsins, a group of Plasmodium-specific, aspartic acid protease enzymes, are involved in many key aspects of parasite biology, and this makes them interesting targets for antimalarial chemotherapy. Among different isoforms, PlmIX serves as an unexplored antimalarial drug target that plays a crucial role along with PlmV and X in the parasite’s survival by digesting hemoglobin in the host’s erythrocytes. In this study, fragment-based virtual screening was performed by modeling the three-dimensional structure of PlmIX and predicting its ligand-binding pocket by using the Sitemap tool. Screening identified the fragments with the XP docking score ≤ −3 kcal/mol from the OTAVA General Fragment Library (≈16,397 fragments), and the selected fragments were chosen for ligand breeding. The resulting ligands (≈69,858 ligands) were subsequently subjected to filtering based on the QikProp properties along with carcinogenicity testing performed using CarcinoPred-EL and then docked in the SP (≈14,078 ligands) as well as XP mode (≈3,104 ligands), and compared with that of control ligands 49C and I0L. The top-ranked ligands were taken further for the calculation of the free energy of binding using Prime MM–GBSA. Overall, a total of six complexes were taken further for MD simulation studies performed at 100 ns to attain a better understanding of the binding mechanisms, and compounds 3 and 4 were found to be the most efficient ones in silico. The analysis of compound 3 revealed that the carbonyl group present in position 1 on the isoindoline moiety (Arg554) was responsible for inhibitory activity against PlmIX. However, the analysis of compound 4 revealed that the amide linkage sandwiched between the phenyl ring and isoquinoline moiety (Lys555 and Ser226) as well as carbonyl oxygen of the carbamoyl group present at position 2 of the pyrazole ring (Gln222) were responsible for PlmIX inhibitory activity, owing to their crucial interactions with key amino acid residues.

ATP mimetics targeting prolyl-tRNA synthetases as a new avenue for antimalarial drug development

The prolyl-tRNA synthetase (PRS) is an essential enzyme for protein translation and a validated target against malaria parasite. We describe five ATP mimetics (L95, L96, L97, L35, and L36) against PRS, exhibiting enhanced thermal stabilities in co-operativity with L-proline. L35 displays the highest thermal stability akin to halofuginone, an established inhibitor of Plasmodium falciparum PRS. Four compounds exhibit nanomolar inhibitory potency against PRS. L35 exhibits the highest potency of ∼1.6nM against asexual-blood-stage (ABS) and ∼100-fold (effective concentration [EC50]) selectivity for the parasite. The macromolecular structures of PfPRS with L95 and L97 in complex with L-pro reveal their binding modes and catalytic site malleability. Arg401 of PfPRS oscillates between two rotameric configurations when in complex with L95, whereas it is locked in one of the configurations due to the larger size of L97. Harnessing such specific and selective chemical features holds significant promise for designing potential inhibitors and expediting drug development efforts.