Plasmodium falciparum proteases as new drug targets with special focus on metalloproteases.

Malaria poses a significant global health threat particularly due to the prevalence of Plasmodium falciparum infection. With the emergence of parasite resistance to existing drugs including the recently discovered artemisinin, ongoing research seeks novel therapeutic avenues within the malaria parasite. Proteases are promising drug targets due to their essential roles in parasite biology, including hemoglobin digestion, merozoite invasion, and egress. While exploring the genomic landscape of Plasmodium falciparum, it has been revealed that there are 92 predicted proteases, with only approximately 14 of them having been characterized. These proteases are further distributed among 26 families grouped into five clans: aspartic proteases, cysteine proteases, metalloproteases, serine proteases, and threonine proteases. Focus on metalloprotease class shows further role in organelle processing for mitochondria and apicoplasts suggesting the potential of metalloproteases as viable drug targets. Holistic understanding of the parasite intricate life cycle and identification of potential drug targets are essential for developing effective therapeutic strategies against malaria and mitigating its devastating global impact.

Malaria: biochemical, physiological, diagnostic, and therapeutic updates.

Background: Malaria has been appraised as a significant vector-borne parasitic disease with grave morbidity and high-rate mortality. Several challenges have been confronting the efficient diagnosis and treatment of malaria. Method: Google Scholar, PubMed, Web of Science, and the Egyptian Knowledge Bank (EKB) were all used to gather articles. Results: Diverse biochemical and physiological indices can mirror complicated malaria e.g., hypoglycemia, dyslipidemia, elevated renal and hepatic functions in addition to the lower antioxidant capacity that does not only destroy the parasite but also induces endothelial damage. Multiple trials have been conducted to improve recent points of care in malaria involving biosensors, lap on-chip, and microdevices technology. Regarding recent therapeutic trials, chemical falcipain inhibitors and plant extracts with anti-plasmodial activities are presented. Moreover, antimalaria nano-medicine and the emergence of nanocarrier (either active or passive) in drug transportation are promising. The combination therapeutic trials e.g., amodiaquine + artemether + lumefantrine are presented to safely counterbalance the emerging drug resistance in addition to the Tafenoquine as a new anti-relapse therapy. Conclusion: Recognizing the pathophysiology indices potentiate diagnosis of malaria. The new points of care can smartly manipulate the biochemical and hematological alterations for a more sensitive and specific diagnosis of malaria. Nano-medicine appeared promising. Chemical and plant extracts remain points of research.

A Case Series: A Mother and Daughter with a Critically Low Hemoglobin Level Resulting from Severe Anemia Secondary to Malaria.

Background: Malaria can lead to anemia, a condition marked by a reduction in red blood cells or lower than typical levels of hemoglobin. This condition mainly affects women and children and, in severe cases, can hinder the cognitive and motor development of children. It also poses significant risks for pregnant women and their unborn children. Case presentation: An 18-month-old girl and her mother, referred from conflict-affected West Wollega, Ethiopia due to severe malaria, were admitted to Assosa General Hospital, Ethiopia, with critical health indicators. The daughter (case 1) had a hemoglobin level of 0.8 g/dL, a red blood cell count of 0.44 × 10^6u/L, an oxygen saturation of 90%, a body temperature of 36.6 °C, a heartbeat of 132 beats per minute, and a respiratory rate of 48 breaths per minute. She displayed signs of pale conjunctivitis and severe palmar paleness, and weighed 7 kg. The mother(case 2), aged 35, also had a history of severe malaria and presented with a critically low hemoglobin level of 2.5g/dL and a red blood cell count of 0.75 × 10^6u/L, with an oxygen saturation of 89%. Blood transfusion and malaria treatment were administered, and by the end of their hospital stay, both cases' symptoms had resolved, and they returned to normal baseline vital signs, including their hemoglobin levels. Conclusions: Severely low hemoglobin levels, worsened by severe malaria, present a significant danger in cases of anemia. As far as I am aware, this might be the lowest hemoglobin level recorded. Promoting awareness, economic empowerment initiatives, alongside routine provision of iron supplements and Prompt malaria diagnosis and treatment to create a comprehensive approach that addresses the multifaceted challenges posed by anemia, ultimately leading to improved health outcomes for vulnerable populations.

Modified peptides and organic metabolites of cyanobacterial origin with antiplasmodial properties.

As etiological agents of malaria disease, Plasmodium spp. parasites are responsible for one of the most severe global health problems occurring in tropical regions of the world. This work involved compiling marine cyanobacteria metabolites reported in the scientific literature that exhibit antiplasmodial activity. Out of the 111 compounds mined and 106 tested, two showed antiplasmodial activity at very low concentrations, with IC50 at 0.1 and 1.5 nM (peptides: dolastatin 10 and lyngbyabellin A, 1.9% of total tested). Examples of chemical derivatives generated from natural cyanobacterial compounds to enhance antiplasmodial activity and Plasmodium selectivity can be found in successful findings from nostocarboline, eudistomin, and carmaphycin derivatives, while bastimolide derivatives have not yet been found. Overall, 57% of the reviewed compounds are peptides with modified residues producing interesting active moieties, such as α- and ß-epoxyketone in camaphycins. The remaining compounds belong to diverse chemical groups such as alkaloids, macrolides, polycyclic compounds, and halogenated compounds. The Dolastatin 10 and lyngbyabellin A, compounds with antiplasmodial high activity, are cytoskeletal disruptors with different protein targets.

Exploiting integrative metabolomics to study host-parasite interactions in Plasmodium infections.

Despite years of research, malaria remains a significant global health burden, with poor diagnostic tests and increasing antimalarial drug resistance challenging diagnosis and treatment. While 'single-omics'-based approaches have been instrumental in gaining insight into the biology and pathogenicity of the Plasmodium parasite and its interaction with the human host, a more comprehensive understanding of malaria pathogenesis can be achieved through 'multi-omics' approaches. Integrative methods, which combine metabolomics, lipidomics, transcriptomics, and genomics datasets, offer a holistic systems biology approach to studying malaria. This review highlights recent advances, future directions, and challenges involved in using integrative metabolomics approaches to interrogate the interactions between Plasmodium and the human host, paving the way towards targeted antimalaria therapeutics and control intervention methods.

Alternative first-line malaria treatment.

Malaria is a disease affecting millions of people, especially in Africa, Asia, and South America, and has become a substantial economic burden. Because malaria is contracted through the bite of a mosquito vector, it is very challenging to prevent. Bed nets and insect repellents are used in some homes; others do not have or use them even when available. Thus, treatment measures are crucial to controlling this disease. Artemisinin-based combination therapy (ACT) is currently the first-line treatment for malaria. ACT has been used for decades, but recently, there has been evidence of potential resistance. This threat of resistance has led to the search for possible alternatives to ACT. In sub-Saharan Africa, Azadirachta indica, or simply neem, is a plant used to treat a variety of ailments, including malaria. Neem is effective against one of the more deadly malaria parasites Plasmodium falciparum. Reports show that neem inhibits microgametogenesis of P. falciparum and interferes with the parasite's ookinete development. Although there is substantial in vitro research on the biological activity of A. indica (neem), there is limited in vivo research. Herein, we discuss the in vivo effects of neem on malaria parasites. With A. indica, the future of malaria treatment is promising, especially for high-risk patients, but further research and clinical trials are required to confirm its biological activity.

Résumé Le paludisme est une maladie qui touche des millions de personnes, notamment en Afrique, en Asie et en Amérique du Sud, et est devenu un problème économique majeur fardeau. Le paludisme étant contracté par la piqûre d'un moustique vecteur, il est très difficile à prévenir. Moustiquaires et insectifuges sont utilisés dans certaines maisons ; d'autres ne les possèdent pas ou ne les utilisent pas même lorsqu'ils sont disponibles. Les mesures thérapeutiques sont donc cruciales pour contrôler cette maladie. La thérapie combinée à base d'artémisinine (ACT) constitue actuellement le traitement de première intention contre le paludisme. L'ACT est utilisé depuis des décennies, mais récemment, il y a eu des preuves d'une résistance potentielle. Cette menace de résistance a conduit à la recherche d'alternatives possibles à l'ACT. En Afrique subsaharienne, Azadirachta indica, ou simplement neem, est une plante utilisée pour traiter diverses maladies, dont le paludisme. Le Neem est efficace contre l'un des des parasites du paludisme plus mortels, Plasmodium falciparum. Des rapports montrent que le neem inhibe la microgamétogenèse de P. falciparum et interfere avec le développement de l'ookinète du parasite. Bien qu'il existe d'importantes recherches in vitro sur l'activité biologique d'A. indica (neem), il existe la recherche in vivo est limitée. Nous discutons ici des effets in vivo du neem sur les parasites du paludisme. Avec A. indica, l'avenir du traitement du paludisme est prometteur, en particulier pour les patients à haut risque, mais des recherches et des essais cliniques supplémentaires sont nécessaires pour confirmer son activité biologique. Mots-clés: Azadirachta indica, paludisme, neem, Plasmodium falciparum.

Betulinic and ursolic acids from Nauclea latifolia roots mediate their antimalarial activities through docking with PfEMP-1 and PfPKG proteins.

BACKGROUND: Chemotherapies target the PfEMP-1 and PfPKG proteins in Plasmodium falciparum, the parasite that causes malaria, in an effort to prevent the disease's high fatality rate. This work identified the phytochemical components of Nauclea latifolia roots and docked the chemical compounds against target proteins, and examined the in vivo antiplasmodial effect of the roots on Plasmodium berghei-infected mice. METHODS: Standard protocols were followed for the collection of the plant's roots, cleaning, and drying of the roots, extraction and fraction preparation, assessment of the in vivo antiplasmodial activity, retrieval of the PfEMP-1 and PfPKG proteins, GCMS, ADME, and docking studies, chromatographic techniques were employed to separate the residual fraction's components, and the Swis-ADME program made it possible to estimate the drug's likeness and pharmacokinetic properties. The Auto Dock Vina 4.2 tool was utilized for molecular docking analysis. RESULTS: The residual fraction showed the best therapeutic response when compared favorably to amodiaquine (80.5%) and artesunate (85.1%). It also considerably reduced the number of parasites, with the % growth inhibition of the parasite at 42.8% (D2) and 83.4% (D5). Following purification, 25 compounds were isolated and characterized with GCMS. Based on their low molecular weights, non-permeation of the blood-brain barrier, non-inhibition of metabolizing enzymes, and non-violation of Lipinski's criteria, betulinic and ursolic acids were superior to chloroquine as the best phytochemicals. Hence, they are lead compounds. CONCLUSION: In addition to identifying the bioactive compounds, ADME, and docking data of the lead compounds as candidates for rational drug design processes as observed against Plasmodium falciparum target proteins (PfEMP-1 and PfPKG), which are implicated in the pathogenesis of malaria, the study has validated that the residual fraction of N. latifolia roots has the best antiplasmodial therapeutic index.

Drug-induced stress mediates Plasmodium falciparum ring-stage growth arrest and reduces in vitro parasite susceptibility to artemisinin.

During blood-stage infection, Plasmodium falciparum parasites are constantly exposed to a range of extracellular stimuli, including host molecules and drugs such as artemisinin derivatives, the mainstay of artemisinin-based combination therapies currently used as first-line treatment worldwide. Partial resistance of P. falciparum to artemisinin has been associated with mutations in the propeller domain of the Pfkelch13 gene, resulting in a fraction of ring stages that are able to survive exposure to artemisinin through a temporary growth arrest. Here, we investigated whether the growth arrest in ring-stage parasites reflects a general response to stress. We mimicked a stressful environment in vitro by exposing parasites to chloroquine or dihydroartemisinin (DHA). We observed that early ring-stage parasites pre-exposed to a stressed culture supernatant exhibited a temporary growth arrest and a reduced susceptibility to DHA, as assessed by the ring-stage survival assay, irrespective of their Pfkelch13 genotype. These data suggest that temporary growth arrest of early ring stages may be a constitutive, Pfkelch13-independent survival mechanism in P. falciparum.IMPORTANCEPlasmodium falciparum ring stages have the ability to sense the extracellular environment, regulate their growth, and enter a temporary growth arrest state in response to adverse conditions such as drug exposure. This temporary growth arrest results in reduced susceptibility to artemisinin in vitro. The signal responsible for this process is thought to be small molecules (less than 3 kDa) released by stressed mature-stage parasites. These data suggest that Pfkelch13-dependent artemisinin resistance and the growth arrest phenotype are two complementary but unrelated mechanisms of ring-stage survival in P. falciparum. This finding provides new insights into the field of P. falciparum antimalarial drug resistance by highlighting the extracellular compartment and cellular communication as an understudied mechanism.

A comprehensive review of antimalarial medicinal plants used by Tanzanians.

CONTEXT: Tanzania has rich medicinal plant (MP) resources, and most rural inhabitants rely on traditional healing practices for their primary healthcare needs. However, available research evidence on antimalarial MPs is highly fragmented in the country. OBJECTIVE: This systematic review compiles ethnomedicinal research evidence on MPs used by Tanzanians as antimalarials. MATERIALS AND METHODS: A systematic web search was conducted using various electronic databases and grey materials to gather relevant information on antimalarial MPs utilized by Tanzanians. The review was per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The data were collected from 25 articles, and MS Excel software was used to analyse relevant ethnobotanical information using descriptive statistics. RESULTS: A total of 227 MPs belonging to 67 botanical families and 180 genera were identified. Fabaceae (15.9%) is the most frequently utilized family. The ethnobotanical recipes analysis indicated leaves (40%) and trees (44%) are the preferred MPs part and life form, respectively. Decoctions (67%) are the dominant preparation method of remedies. Of the recorded MPs, 25.9% have been scientifically investigated for antimalarial activities with positive results. However, 74.1% of MPs have no scientific records on antimalarial activities, but they could be potential sources of remedies. CONCLUSIONS: The study discloses a wealth of antimalarial MPs possessed by Tanzanians and suggests a need for research to authenticate the healing potential of antimalarial compounds from the unstudied MPs. Additionally, it indicates that some of the presented MPs are potential sources for developing safe, effective and affordable antimalarial drugs.

Seasonal Malaria Chemoprevention Therapy in Children Up To 9 Years of Age: Protocol for a Cluster-Randomized Trial Study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended by the World Health Organization for the sub-Sahel region in sub-Saharan Africa for preventing malaria in children 3 months old to younger than 5 years. Since 2016, the Malian National Malaria Control Program has deployed SMC countrywide during its high malaria transmission season at a rate of 4 monthly cycles annually. The standard SMC regimen includes sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ). Resistance against SP is suspected to be rising across West Africa; therefore, assessing the effectiveness of an alternative antimalarial drug for SMC is needed to provide a second-line regimen when it is ultimately needed. It is not well understood whether SMC effectively prevents malaria in children aged 5 years or older. OBJECTIVE: The primary goal of the study is to compare 2 SMC regimens (SP-AQ and dihydroartemisinin-piperaquine [DHA-PQ]) in preventing uncomplicated Plasmodium falciparum malaria in children 3 months to 9 years old. Secondly, we will assess the possible use of DHA-PQ as an alternative SMC drug in areas where resistance to SP or AQ may increase following intensive use. METHODS: The study design is a 3-arm cluster-randomized design comparing the SP-AQ and DHA-PQ arms in 2 age groups (younger than 5 years and 5-9 years) and a control group for children aged 5-9 years. Standard SMC (SP-AQ) for children younger than 5 years was provided to the control arm, while SMC with SP-AQ was delivered to children aged 3 months to 9 years (arm 2), and SMC with DHA-PQ will be implemented in study arm 3 for children up to 9 years of age. The study was performed in Mali's Koulikoro District, a rural area in southwest Mali with historically high malaria transmission rates. The study's primary outcome is P falciparum incidence for 2 SMC regimens in children up to 9 years of age. Should DHA-PQ provide an acceptable alternative to SP-AQ, a plausible second-line prevention option would be available in the event of SP resistance or drug supply shortages. A significant byproduct of this effort included bolstering district health information systems for rapid identification of severe malaria cases. RESULTS: The study began on July 1, 2019. Through November 2022, a total of 4556 children 3 months old to younger than 5 years were enrolled. Data collection ended in spring 2023, and the findings are expected to be published later in early 2024. CONCLUSIONS: Routine evaluation of antimalarial drugs is needed to establish appropriate SMC age targets. The study goals here may impact public health policy and provide alternative therapies in the event of drug shortages or resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT04149106, https://clinicaltrials.gov/ct2/show/NCT04149106. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51660.

Identification of starvation-mimetic bioactive phytocomponent from Withania somnifera using in-silico molecular modelling and flow cytometry-based analysis for the management of malaria.

Multidrug resistance episodes in malaria increased from 3.9% to 20% from 2015 to 2019. Synchronizing the clinical manifestation in chronological sequence led to a unique impression on glucose demand (increased up to 100-fold) by the parasite-infected RBCs. Hence, restriction in the glucose uptake to parasite-infected RBCs could be an alternative approach to conquer the global burden of malaria to a greater extent. A C28 steroidal lactone Withaferin A (WS-3) isolated from Withania somnifera leave extract shows better thermodynamically stable interactions with the glucose transporters (GLUT-1 and PfHT) to standard drugs metformin and lopinavir. MD simulations for a trajectory period of 100 ns reflect stable interactions with the interactive amino acid residues such as Pro141, Gln161, Gln282, Gln283, Trp388, Phe389, and Phe40, Asn48, Phe85, His168, Gln169, Asn311 which potentiating inhibitory activity of WS-3 against GLUT-1 and PfHT respectively. WS-3 was non-hemotoxic (%hemolysis <5%) for a high concentration of up to 1 mg/ml in the physiological milieu. However, the %hemolysis significantly increased up to 30.55 ± 0.929% in a parasitophorous simulated environment (pH 5.0). Increased hemolysis of WS-3 could be due to the production of ROS in an acidic environment. Further, the inhibitory activity of WS-3 against both glucose transporters was supported with flow cytometry-based analysis of parasite-infected RBCs. Results show that WS-3 has low mean fluorescence intensities for both target proteins compared to conventional drugs, suggesting a potential sugar transporter inhibitor against GLUT-1 and PfHT for managing malaria. Communicated by Ramaswamy H. Sarma.

Malaria Is Associated with Diminished Levels of Ascorbic Acid: A Systematic Review and Meta-Analysis.

Background: It is still unclear how ascorbic acid levels relate to the pathogenesis of malaria. This systematic review synthesized different ascorbic acid levels in malaria patients with different severity levels of malaria and Plasmodium species. Methods: The systematic review protocol was registered in the PROSPERO database (CRD42023394849). A systematic search of PubMed, Embase, MEDLINE, Ovid, Scopus, and Google Scholar was conducted to identify studies that reported ascorbic acid and malaria. The pooled standardized mean difference (Cohen's d) with 95% confidence intervals (CIs) was calculated using the random-effects model. Results: A total of 1480 articles were obtained from the searches of the databases, and 30 studies were included for syntheses. The meta-analysis revealed that patients with malaria had lower levels of ascorbic acid than those without malaria or uninfected controls (p < 0.01, Cohen's d = -3.71, 95% CI = -4.44 to -2.98, I2 = 98.87%, 30 studies). Comparable levels of ascorbic acid were observed between patients with severe malaria and those with nonsevere malaria (p = 0.06, Cohen's d = -1.39, 95% CI = -2.85 to 0.07, I2 = 96.58%, 4 studies). Similarly, levels of ascorbic acid were comparable between patients with Plasmodium falciparum and Plasmodium vivax malaria (p = 0.34, Cohen's d = -1.06, 95% CI = -3.23 to 1.12, I2 = 97.30%, 3 studies). Conclusions: The meta-analysis reveals diminished levels of ascorbic acid in malaria cases. Manipulating the host's nutritional status, such as by supplementing it with ascorbic acid to restore reactive oxygen species balance, may alter the progression of malarial infection and prevention of disease severity. Antioxid. Redox Signal. 40, 460-469.

Evaluation of Andrographis paniculata-supplemented Diet on the reproductive indices of Plasmodium berghei-infected mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The King of Bitters (Andrographis paniculata) is a plant used to cure a wide range of infectious diseases which includes malaria, fever and others. However, there is a paucity of scientific evidence of its effect on male reproductive indices during malaria treatment. AIM OF THE STUDY: The aim of this study is to evaluate the effect of supplemented diet on antiplasmodial, hematological and male reproductive indices in mice infected with Plasmodium berghei. MATERIALS AND METHODS: Aqueous extract of A. paniculata (King of Bitters, KGB) was prepared and the total phenol and flavonoid contents were determined. Forty-two mice, weighing 20-25 g, were distributed into 7 groups consisting of 6 mice each. The mice were innoculated with strain NK65 Plasmodium berghei (Chloroquine, CQ sensitive) and the parasitemia suppression was assessed. The mice were fed with the dietary supplementation of KGB at varying inclusions (2.5%, 5%, 7.5%, and 10%) and administered 10 mg/kg CQ (which served as the positive control) for 5 consecutive days after infection was established. The reactive malondialdeahyde (MDA), antioxidant [superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH)] and the hematological (hemoglobin, packed cell volume and red blood cell) parameters in the infected mice were determined. The reproductive indices (serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sperm count, sperm motility, and sperm viability) and testis histopathology were also assessed. RESULT: The result revealed that KGB had a total phenol content of 32.55 mgGAE/g and total flavonoid content of 19.71 mgQUE/g. The infected mice treated with the dietary supplementation of KGB showed significantly decreased (p < 0.05) parasitaemia and MDA levels. Furthermore, the 7.5% dietary inclusion showed significant improvement in the antioxidant, hematological and reproductive indices as well as the restoration of testis morphology as seen in the histopathology plate of the infected mice treated with KGB. Hence, this study suggests that the KGB- supplemented diet (7.5%) may be a potential alternative and complementary therapy in the treatment of malaria infection and reproductive disorders.

Exploring the efficacy of ethnomedicinal plants of Himalayan region against the malaria parasite.

ETHNOPHARMACOLOGICAL RELEVANCE: Plasmodium falciparum multi-drug resistant (MDR) strains are a great challenge to global health care. This predicament implies the urgent need to discover novel antimalarial drugs candidate from alternative natural sources. The Himalaya constitute a rich repository of medicinal plants which have been used traditionally in the folklore medicine since ages and having no scientific evidence for their activity. Crambe kotschyana Boiss. and Eremurus himalaicus Baker are used for their antipyretic and hepatoprotective properties in Kinnaur district of Himachal Pradesh, India. AIM OF THE STUDY: This study would investigate the antiplasmodial efficacy of C. kotschyana and E. himalaicus extracts, their fractions and active components using in vitro, in vivo and in silico approaches to provide a scientific insight into their activity. METHODS: The methanol extracts of C. kotschyana (CKME) and E. himalaicus (EHME) were prepared by maceration followed by fractionation using ethyl acetate. The isolation of flavonoid glycosides isorhamnetin-3, 7-di-O-glucoside from C. kotschyana and luteolin-6-C-glucoside (isoorientin) from E. himalaicus was carried out by antiplasmodial activity-guided isolation. In vitro antimalarial activity was assessed by WHO method while in vitro cytotoxicity was ascertained employing the MTT assay. Molecular docking and molecular dynamics simulation were performed using the Glide module of Schrödinger Software and Gromacs-2022 software package respectively. In vivo curative activity was assessed by Ryley and Peters method. RESULTS: The methanol extracts of both the plants illustrated the best antiplasmodial activity followed by the ethyl acetate fractions. Iso-orientin (IC50 6.49 µg/ml) and Isorhamnetin-3,7-di-O-glucoside (IC50 9.22 µg/ml) illustrated considerable in vitro activity even against P. falciparum resistant strain. Extracts/fractions as well as the isolated compounds were found to be non-toxic with CC50 > 640 µg/ml. Molecular docking studies were performed with these 2 O-glucosides against four malaria targets to understand the binding pose of these molecules and the results suggested that these molecules have selectivity for lactate dehydrogenase enzyme. CKME and EHME exhibited curative activity in vivo along with increase in Mean Survival Time of mice. CONCLUSION: The research delineated the scientific evidence that both the therapeutic herbs possessed antimalarial activity and notably, bioactive compounds responsible to exhibit the antimalarial activity have been isolated, identified and characterized. Further studies are underway to assess the antiplasmodial efficacy of isolated compounds alone and in combination with standard antimalarials.

In silico modeling revealed phytomolecules derived from Cymbopogon citratus (DC.) leaf extract as promising candidates for malaria therapy.

The emergence of varying levels of resistance to currently available antimalarial drugs significantly threatens global health. This factor heightens the urgency to explore bioactive compounds from natural products with a view to discovering and developing newer antimalarial drugs with novel mode of actions. Therefore, we evaluated the inhibitory effects of sixteen phytocompounds from Cymbopogon citratus leaf extract against Plasmodium falciparum drug targets such as P. falciparum circumsporozoite protein (PfCSP), P. falciparum merozoite surface protein 1 (PfMSP1) and P. falciparum erythrocyte membrane protein 1 (PfEMP1). In silico approaches including molecular docking, pharmacophore modeling and 3D-QSAR were adopted to analyze the inhibitory activity of the compounds under consideration. The molecular docking results indicated that a compound swertiajaponin from C. citratus exhibited a higher binding affinity (-7.8 kcal/mol) to PfMSP1 as against the standard artesunate-amodiaquine (-6.6 kcal/mol). Swertiajaponin also formed strong hydrogen bond interactions with LYS29, CYS30, TYR34, ASN52, GLY55 and CYS28 amino acid residues. In addition, quercetin another compound from C. citratus exhibited significant binding energies -6.8 and -8.3 kcal/mol with PfCSP and PfEMP1, respectively but slightly lower than the standard artemether-lumefantrine with binding energies of -7.4 kcal/mol against PfCSP and -8.7 kcal/mol against PfEMP1. Overall, the present study provides evidence that swertiajaponin and other phytomolecules from C. citratus have modulatory properties toward P. falciparum drug targets and thus may warrant further exploration in early drug discovery efforts against malaria. Furthermore, these findings lend credence to the folkloric use of C. citratus for malaria treatment.Communicated by Ramaswamy H. Sarma.

Brazilian plants with antimalarial activity: A review of the period from 2011 to 2022.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria continues to be a serious global public health problem in subtropical and tropical countries of the world. The main drugs used in the treatment of human malaria, quinine and artemisinin, are isolates of medicinal plants, making the use of plants a widespread practice in countries where malaria is endemic. Over the years, due to the increased resistance of the parasite to chloroquine and artemisinin in certain regions, new strategies for combating malaria have been employed, including research with medicinal plants. AIM: This review focuses on the scientific production regarding medicinal plants from Brazil whose antimalarial activity was evaluated during the period from 2011 to 2022. 2. METHODOLOGY: For this review, four electronic databases were selected for research: Pubmed, ScienceDirect, Scielo and Periódicos CAPES. Searches were made for full texts published in the form of scientific articles written in Portuguese or English and in a digital format. In addition, prospects for new treatments as well as future research that encourages the search for natural products and antimalarial derivatives are also presented. RESULTS: A total of 61 publications were encountered, which cited 36 botanical families and 92 species using different Plasmodium strains in in vitro and in vivo assays. The botanical families with the most expressive number of species found were Rubiaceae, Apocynaceae, Fabaceae and Asteraceae (14, 14, 9 and 6 species, respectively), and the most frequently cited species were of the genera Psychotria L. (8) and Aspidosperma Mart. (12), which belong to the families Rubiaceae and Apocynaceae. Altogether, 75 compounds were identified or isolated from 28 different species, 31 of which are alkaloids. In addition, the extracts of the analyzed species, including the isolated compounds, showed a significant reduction of parasitemia in P. falciparum and P. berghei, especially in the clones W2 CQ-R (in vitro) and ANKA (in vivo), respectively. The Brazilian regions with the highest number of species analyzed were those of the north, especially the states of Pará and Amazonas, and the southeast, especially the state of Minas Gerais. CONCLUSION: Although many plant species with antimalarial potential have been identified in Brazil, studies of new antimalarial molecules are slow and have not evolved to the production of a phytotherapeutic medicine. Given this, investigations of plants of traditional use and biotechnological approaches are necessary for the discovery of natural antimalarial products that contribute to the treatment of the disease in the country and in other endemic regions.

Development and Characterization of Novel Chitosan-Coated Curcumin Nanophytosomes for Treating Drug-Resistant Malaria.

This study aimed at enhancing the efficacy of curcumin (CR) by formulating and coating it with chitosan. In silico molecular docking studies revealed that CR exhibited almost similar and low binding energies when compared to artemisinin, indicating high stability at the target site. It can be confirmed that CR is effective in treating and reducing Plasmodium falciparum parasites. Fourier transform infrared studies confirmed that there was a shift and disappearance of some drug peaks in the formulation which revealed complexation with phospholipids. The F2EXT3-developed formulation exhibited greater solubility (24.31 ± 3.47 µg/mL) when compared to pure CR (7.99 ± 1.95 µg/mL). Proton nuclear magnetic resonance studies confirmed the formation of Curcumin-phospholipid hydrogen bonding in F2EXT3. The in vitro drug release studies revealed that the developed formulation F2EXT3 exhibited better drug release at 71.98% at 48 h; this might be due to the effective entrapment efficiency of the drug inside the phospholipid, presence of polyethylene glycol 4000 and chitosan further assisted in sustained release of the drug. Scanning electron microscopy studies revealed that optimized F2EXT3 CR nanophytosomes were nearly spherical with narrow size distribution and smooth surface. The zeta potential of the F2EXT3 showed -3.5 mV. Stability studies revealed that the formulation remained stable even after 6 months. It was observed from the hemin assay that CR and F2EXT3 exhibited (50 µg/mL curcumin) exhibited IC50 values of 47 ± 2.45 and 22 ± 1.58 µM, respectively. Further in vivo antimalarial activity on resistant and sensitive strains needs to be performed to evaluate the efficacy of the developed formulation.

Predicting Plasmodium falciparum kinase inhibitors from antimalarial medicinal herbs using computational modeling approach.

Malaria remains a significant public health challenge, with resistance to available drugs necessitating the development of novel therapies targeting invasion-dependent proteins. Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK-1) is essential for host erythrocyte invasion and parasite asexual development. This study screened a library of 490 compounds using computational methods to identify potential PfCDPK-1 inhibitors. Three compounds; 17-hydroxyazadiradione, Picracin, and Epicatechin-gallate derived from known antimalarial botanicals, showed potent inhibitory effects on PfCDPK-1. These compounds exhibited better binding affinities (-8.8, -9.1, -9.3 kCal/mol respectively), pharmacokinetics, and physicochemical properties than the purported inhibitory standard of PfCDPK-1, Purfalcamine. Molecular dynamics simulations (50 ns) and molecular mechanics analyses confirmed the stability and binding rigidity of these compounds at the active pocket of PfCDPK-1. The results suggest that these compounds are promising pharmacological targets with potential therapeutic effects for malaria treatment/management without undesirable side effects. Therefore, this study provides new insights into the development of effective antimalarial agents targeting invasion-dependent proteins, which could help combat the global malaria burden. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00175-z.

DHA-rich fish oil plays a protective role against experimental cerebral malaria by controlling inflammatory and mechanical events from infection.

Every year, thousands of children, particularly those under 5 years old, die because of cerebral malaria (CM). Following conventional treatment, approximately 25% of surviving individuals have lifelong severe neurocognitive sequelae. Therefore, improved conventional therapies or effective alternative therapies that prevent the severe infection are crucial. Omega-3 (Ω-3) polyunsaturated fatty acids (PUFAs) are known to have antioxidative and anti-inflammatory effects and protect against diverse neurological disorders, including Alzheimer's and Parkinson's diseases. However, little is known regarding the effects of Ω-3 PUFAs against parasitic infections. In this study, C57BL/6 mice received supplemental treatment of a fish oil rich in the Ω-3 PUFA, docosahexaenoic acid (DHA), which was started 15 days prior to infection with Plasmodium berghei ANKA and was maintained until the end of the study. Animals treated with the highest doses of DHA, 3.0 and 6.0 g/kg body weight, had 60 and 80% chance of survival, respectively, while all nontreated mice died by the 7th day postinfection due to CM. Furthermore, the parasite load during the critical period for CM development (5th to 11th day postinfection) was controlled in treated mice. However, after this period all animals developed high levels of parasitemia until the 20th day of infection. DHA treatment also effectively reduced blood-brain barrier (BBB) damage and brain edema and completely prevented brain hemorrhage and vascular occlusion. A strong anti-inflammatory profile was observed in the brains of DHA-treated mice, as well as, an increased number of neutrophil and reduced number of CD8+ T leukocytes in the spleen. Thus, this is the first study to demonstrate that the prophylactic use of DHA-rich fish oil exerts protective effects against experimental CM, reducing the mechanical and immunological events caused by the P. berghei ANKA infection.

Disability inclusion in malaria services in western Tanzania: A rapid barrier analysis.

Background: Persons with disabilities generally face greater challenges in accessing healthcare and interventions compared with the general population. Malaria is one of the diseases that can seriously affect individuals with disabilities, as it requires early diagnosis and prompt treatment. Objective: This study explores the extent to which locally available malaria services and interventions are inclusive of persons with disabilities and identifies associated access barriers. Method: A qualitative case study focusing on social, cultural and health system factors associated with the inclusion of persons with disabilities in malaria services was conducted in Kigoma Region, western Tanzania. Thematic analysis of emerging themes identified barriers affecting access to locally available malaria services and interventions. Results: Inclusion of persons with disabilities in planning, implementation and reporting of health issues in different malaria programmes was reported to be limited. Persons with disabilities were unable to access malaria services because of different barriers such as the distance of the service provision sites, communication and information issues and a lack of financial resources. Conclusion: Persons with disabilities are widely excluded from malaria care provision across the entire health services paradigm, impacting access and utilisation to this vulnerable population. Barriers to malaria service access among persons with disabilities were physical, attitudinal, financial and informational. Contribution: The findings of this study identify that malaria intervention stakeholders need to take a holistic approach and fully involve individuals with disabilities at all levels and scope of malaria service planning and provision.