-
RSC Advances Jun 2024To combat resistance against current antimalarials, modifying key pharmacophores and exploring novel parasite-specific drug targets remained one of the key drug design...
To combat resistance against current antimalarials, modifying key pharmacophores and exploring novel parasite-specific drug targets remained one of the key drug design strategies. The resistance to quinoline-based antimalarials arises often due to the efflux of the drug. Hence, the development of newer agents containing bulkier pharmacophores will enable medicinal chemists to counteract drug resistance. In view of this, herein we designed bulkier quinoline-furanone hybrids. Initially, virtual drug-likeness and ADMET screening were conducted to optimize physicochemical properties followed by docking of the hybrids against the lactate dehydrogenase (LDH) enzyme. The most potent hybrids that emerged from the computational screening were synthesized and screened for their bioactivity against the resistant strain of through Schizont Maturation Inhibition assays. Among the compounds tested, 5g and 6e demonstrated the best activity, with IC values similar to chloroquine (CQ), and 5g exhibited superior LDH inhibition compared to CQ. Compounds 5f, 7a, and 7f showed IC values comparable to CQ and moderate LDH inhibition. Structure-activity relationship (SAR) analysis revealed that halogen substitutions, particularly Br and Cl, enhanced antimalarial activity, while strong electron-withdrawing (-NO) or -donating (-OH) groups led to diminished activity. Additionally, bulkier aromatic substitutions were favoured for antimalarial activity and LDH inhibition. The investigation successfully found potent anti-plasmodial quinoline-furanone hybrids, demonstrating promising prospects for combating malaria.
PubMed: 38867738
DOI: 10.1039/d4ra01804d -
Malaria Journal Jun 2024Malaria remains a major global health problem although there was a remarkable achievement between 2000 and 2015. Malaria drug resistance, along with several other...
BACKGROUND
Malaria remains a major global health problem although there was a remarkable achievement between 2000 and 2015. Malaria drug resistance, along with several other factors, presents a significant challenge to malaria control and elimination efforts. Numerous countries in sub-Saharan Africa have documented the presence of confirmed or potential markers of partial resistance against artemisinin, the drug of choice for the treatment of uncomplicated Plasmodium falciparum malaria. The World Health Organization (WHO) recommends regular surveillance of artemisinin therapeutic efficacy to inform policy decisions.
METHODS
This study aimed to evaluate the therapeutic efficacy of artemether-lumefantrine (AL), which is the first-line treatment for uncomplicated P. falciparum malaria in Ethiopia since 2004. Using a single-arm prospective evaluation design, the study assessed the clinical and parasitological responses of patients with uncomplicated P. falciparum malaria in Metehara Health Centre, central-east Ethiopia. Out of 2332 malaria suspects (1187 males, 1145 females) screened, 80 (50 males, 30 females) were enrolled, followed up for 28 days, and 73 (44 males, 29 females) completed the follow up. The study was conducted and data was analysed by employing the per-protocol and Kaplan-Meier analyses following the WHO Malaria Therapeutic Efficacy Evaluation Guidelines 2009.
RESULTS
The results indicated rapid parasite clearance and resolution of clinical symptoms, with all patients achieving complete recovery from asexual parasitaemia and fever by day (D) 3. The prevalence of gametocytes decreased from 6.3% on D0 to 2.5% on D2, D3, D7, and ultimately achieving complete clearance afterward.
CONCLUSION
The overall cure rate for AL treatment was 100%, demonstrating its high efficacy in effectively eliminating malaria parasites in patients. No serious adverse events related to AL treatment were reported during the study, suggesting its safety and tolerability among the participants. These findings confirm that AL remains a highly efficacious treatment for uncomplicated P. falciparum malaria in the study site after 20 years of its introduction in Ethiopia.
Topics: Humans; Ethiopia; Malaria, Falciparum; Artemether, Lumefantrine Drug Combination; Male; Female; Antimalarials; Adult; Adolescent; Young Adult; Child, Preschool; Child; Prospective Studies; Middle Aged; Infant; Artemisinins; Fluorenes; Treatment Outcome; Ethanolamines; Aged; Drug Combinations; Plasmodium falciparum
PubMed: 38867217
DOI: 10.1186/s12936-024-04991-2 -
Nature Jul 2024Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular...
Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.
Topics: Humans; History, Ancient; Genome, Protozoan; Plasmodium falciparum; Plasmodium vivax; Malaria; Europe; Genome, Mitochondrial; Plasmodium; Americas; DNA, Ancient; Malaria, Falciparum; Malaria, Vivax; Asia; South America
PubMed: 38867050
DOI: 10.1038/s41586-024-07546-2 -
Microbiology Spectrum Jul 2024A hallmark of cerebral malaria (CM) is sequestration of -infected erythrocytes (IE) within the brain microvasculature. Binding of IE to endothelium reduces microvascular...
UNLABELLED
A hallmark of cerebral malaria (CM) is sequestration of -infected erythrocytes (IE) within the brain microvasculature. Binding of IE to endothelium reduces microvascular flow and, combined with an inflammatory response, perturbs endothelial barrier function, resulting in breakdown of the blood-brain barrier (BBB). Cytoadherence leads to activation of the endothelium and alters a range of cell processes affecting signaling pathways, receptor expression, coagulation, and disruption of BBB integrity. Here, we investigated whether CM-derived parasites elicit differential effects on human brain microvascular endothelial cells (HBMECs), as compared to uncomplicated malaria (UM)-derived parasites. Patient-derived IE from UM and CM clinical cases, as well as non-binding skeleton-binding protein 1 knockout parasites, were overlaid onto tumour necrosis factor (TNF)-activated HBMECs. Gene expression analysis of endothelial responses was performed using probe-based assays of a panel of genes involved in inflammation, apoptosis, endothelial barrier function, and prostacyclin synthesis pathway. We observed a significant effect on endothelial transcriptional responses in the presence of IE, yet there was no significant correlation between HBMEC responses and type of clinical syndrome (UM or CM). Furthermore, there was no correlation between HBMEC gene expression and both binding itself and level of IE binding to HBMECs, as we detected the same change in endothelial responses when employing both binding and non-binding parasites. Our results suggest that interaction of IE with endothelial cells in this co-culture model induces some endothelial responses that are independent of clinical origin and independent of the expression of the major variant antigen erythrocyte membrane protein 1 on the IE surface.
IMPORTANCE
Cerebral malaria (CM) is the most prevalent and deadly complication of severe infection. A hallmark of this disease is sequestration of -infected erythrocytes (IE) in brain microvasculature that ultimately results in breakdown of the blood-brain barrier. Here, we compared the effect of parasites derived from uncomplicated malaria (UM) and CM cases on the relative gene expression of human brain microvascular endothelial cells (HBMECs) for a panel of genes. We observed a significant effect on the endothelial transcriptional response in the presence of IE, yet there is no significant correlation between HBMEC responses and the type of clinical syndrome (UM or CM). Furthermore, there was no correlation between HBMEC gene expression and both binding itself and the level of IE binding to HBMECs. Our results suggest that interaction of IE with endothelial cells induces endothelial responses that are independent of clinical origin and not entirely driven by surface erythrocyte membrane protein 1 expression.
Topics: Plasmodium falciparum; Humans; Endothelial Cells; Malaria, Falciparum; Malaria, Cerebral; Brain; Blood-Brain Barrier; Erythrocytes
PubMed: 38864616
DOI: 10.1128/spectrum.00727-24 -
Frontiers in Immunology 2024Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both...
BACKGROUND
Despite decades of effort, malaria remains a leading killer of children. The absence of a highly effective vaccine and the emergence of parasites resistant to both diagnosis as well as treatment hamper effective public health interventions.
METHODS AND RESULTS
To discover new vaccine candidates, we used our whole proteome differential screening method and identified PfGBP130 as a parasite protein uniquely recognized by antibodies from children who had developed resistance to infection but not from those who remained susceptible. We formulated PfGBP130 as lipid encapsulated mRNA, DNA plasmid, and recombinant protein-based immunogens and evaluated the efficacy of murine polyclonal anti-PfGBP130 antisera to inhibit parasite growth in vitro. Immunization of mice with PfGBP130-A (aa 111-374), the region identified in our differential screen, formulated as a DNA plasmid or lipid encapsulated mRNA, but not as a recombinant protein, induced antibodies that inhibited RBC invasion . mRNA encoding the full ectodomain of PfGBP130 (aa 89-824) also generated parasite growth-inhibitory antibodies.
CONCLUSION
We are currently advancing PfGBP130-A formulated as a lipid-encapsulated mRNA for efficacy evaluation in non-human primates.
Topics: Animals; Plasmodium falciparum; Antibodies, Protozoan; Mice; Erythrocytes; Malaria, Falciparum; Humans; Malaria Vaccines; Protozoan Proteins; Antigens, Protozoan; Immunization; Female
PubMed: 38863702
DOI: 10.3389/fimmu.2024.1350560 -
Tropical Medicine and Health Jun 2024The national malaria programme of Cambodia targets the rapid elimination of all human malaria by 2025. As clinical cases decline to near-elimination levels, a key...
INTRODUCTION
The national malaria programme of Cambodia targets the rapid elimination of all human malaria by 2025. As clinical cases decline to near-elimination levels, a key strategy is the rapid identification of malaria outbreaks triggering effective action to interrupt local transmission. We report a comprehensive, multipronged management approach in response to a 2022 Plasmodium falciparum outbreak in Kravanh district, western Cambodia.
METHODS
The provincial health department of Pursat in conjunction with the Center for Parasitology, Entomology and Malaria Control (CNM) identified villages where transmission was occurring using clinical records, and initiated various interventions, including the distribution of insecticide-treated bed nets, running awareness campaigns, and implementing fever screening with targeted drug administration. Health stations were set up at forest entry points, and later, targeted drug administrations with artesunate-pyronaridine (Pyramax) and intermittent preventive treatment for forest goers (IPTf) were implemented in specific village foci. Data related to adherence and adverse events from IPTf and TDA were collected. The coverage rates of interventions were calculated, and local malaria infections were monitored.
RESULTS
A total of 942 individuals were screened through active fever surveillance in villages where IPTf and TDA were conducted. The study demonstrated high coverage and adherence rates in the targeted villages, with 92% (553/600) coverage in round one and 65% (387/600) in round two. Adherence rate was 99% (551/553) in round one and 98% (377/387) in round two. The study found that forest goers preferred taking Pyramax over repeated testing consistent with the coverage rates: 92% in round one compared to 65% in round two. All individuals reachable through health stations or mobile teams reported complete IPTf uptake. No severe adverse events were reported. Only six individuals reported mild adverse events, such as loss of energy, fever, abdominal pain, diarrhoea, and muscle aches. Two individuals attributed their symptoms to heavy alcohol intake following prophylaxis.
CONCLUSIONS
The targeted malaria outbreak response demonstrated high acceptability, safety, and feasibility of the selected interventions. Malaria transmission was rapidly controlled using the available community resources. This experience suggests the effectiveness of the programmatic response for future outbreaks.
PubMed: 38863067
DOI: 10.1186/s41182-024-00607-2 -
Nature Reviews. Immunology Jun 2024Malaria, caused by infection with Plasmodium parasites, drives multiple regulatory responses across the immune landscape. These regulatory responses help to protect... (Review)
Review
Malaria, caused by infection with Plasmodium parasites, drives multiple regulatory responses across the immune landscape. These regulatory responses help to protect against inflammatory disease but may in some situations hamper the acquisition of adaptive immune responses that clear parasites. In addition, the regulatory responses that occur during Plasmodium infection may negatively affect malaria vaccine efficacy in the most at-risk populations. Here, we discuss the specific cellular mechanisms of immunoregulatory networks that develop during malaria, with a focus on knowledge gained from human studies and studies that involve the main malaria parasite to affect humans, Plasmodium falciparum. Leveraging this knowledge may lead to the development of new therapeutic approaches to increase protective immunity to malaria during infection or after vaccination.
PubMed: 38862638
DOI: 10.1038/s41577-024-01041-5 -
EMBO Molecular Medicine Jun 2024Parasites, such as the malaria parasite P. falciparum, are critically dependent on host nutrients. Interference with nutrient uptake can lead to parasite death and,...
Parasites, such as the malaria parasite P. falciparum, are critically dependent on host nutrients. Interference with nutrient uptake can lead to parasite death and, therefore, serve as a successful treatment strategy. P. falciparum parasites cannot synthesise cholesterol, and instead source this lipid from the host. Here, we tested whether cholesterol uptake pathways could be 'hijacked' for optimal drug delivery to the intracellular parasite. We found that fluorescent cholesterol analogues were delivered from the extracellular environment to the intracellular parasite. We investigated the uptake and inhibitory effects of conjugate compounds, where proven antimalarial drugs (primaquine and artesunate) were attached to steroids that mimic the structure of cholesterol. These conjugated antimalarial drugs improved the inhibitory effects against multiple parasite lifecycle stages, multiple parasite species, and drug-resistant parasites, whilst also lowering the toxicity to human host cells. Steroids with introduced peroxides also displayed antimalarial activity. These results provide a proof-of-concept that cholesterol mimics can be developed as a drug delivery system against apicomplexan parasites with the potential to improve drug efficacy, increase therapeutic index, and defeat drug resistance.
PubMed: 38862600
DOI: 10.1038/s44321-024-00087-1 -
ACS Infectious Diseases Jun 2024ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, , exhibits reduced crystallinity and improved in...
ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, , exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe , a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant parasites. , a prodrug of with diminished crystallinity, is more effective vs murine malaria than its progenitor by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.
PubMed: 38862127
DOI: 10.1021/acsinfecdis.4c00140 -
Journal of Korean Medical Science Jun 2024Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the...
Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per μL of blood (p/μL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/μL. However, at follow-up, parasite density increased to 7,630 p/μL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.
Topics: Humans; Malaria, Falciparum; Ghana; Antimalarials; Middle Aged; Male; Plasmodium falciparum; Proguanil; Atovaquone; Travel; Artemisinins; Artesunate; Parasitemia; Doxycycline; Drug Combinations; Treatment Failure; Artemether, Lumefantrine Drug Combination
PubMed: 38859743
DOI: 10.3346/jkms.2024.39.e186