Malaria

Epidemiology, Clinical features, Severe malaria, Differential diagnosis, Diagnosis, General management, Antimalarial chemotherapy, Treatment of severe malaria, Prevention, Monitoring antimalarial drug resistance

PERSISTENCE OF MALARIALANTIGEN FOLLOWING ANTIMALARIAL CHEMOTHERAPY IN KOLKATA, WEST BENGAL

Early diagnosis and complete treatment is one of the important aspects of malaria elimination programme worldwide. In many areas the diagnosis is based on detection of malarial antigen using commercially available rapid diagnostic kits. The problem remains with persistence of antigen following parasite clearance by proper treatment. The present work was undertaken to study the pattern of persistent antigen of P. vivax and P. falciparum following antimalarial treatment. Atotal of 300 microscopically positive mono-infected with P. vivax (160) and P. vivax (140) patients were recruited, treated with antimalarial drugs and followed up on day 3, 7, 14, 21 and 28 for persistent parasites and antigen. P. vivax specic pLDH antigen was disappeared from peripheral blood within 14 days post treatment period. P. falciparum specic HRP-2 antigen was persisted even after 28 days of treatment. Depending only on antigen based diagnosis, attention should be paid before treatment, particularly in areas with high malaria transmission

Antimalarial drug discovery: from quinine to the most recent promising clinical drug candidates

: Malaria is a tropical threatening disease caused by Plasmodium parasites, resulting in 409,000 deaths in 2019. The delay of mortality and morbidity has been compounded by the widespread of drug resistant parasites from Southeast Asia since two decades. The emergence of artemisinin-resistant Plasmodium in Africa, where most cases are accounted, highlights the urgent need for new medicines. In this effort, the World Health Organization and Medicines for Malaria Venture joined to define clear goals for novel therapies and characterized the target candidate profile. This ongoing search for new treatments is based on imperative labor in medicinal chemistry which is summarized here with particular attention to hit-to-lead optimizations, key properties, and modes of action of these novel antimalarial drugs. This review, after presenting the current antimalarial chemotherapy, from quinine to the latest marketed drugs, focuses in particular on recent advances of the most promising antimalarial candidates in clinical and preclinical phases.

Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda

Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa1–4. Here we genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance5,6, in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda7. While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.

Combined CADD and Virtual Screening to Identify Novel Nonpeptidic Falcipain-2 Inhibitors

Background: : Plasmodium falciparum is the most dangerous and widespread disease-causing species of malaria. Falcipain-2 (FP2) of Plasmodium falciparum, is a potential target for antimalarial chemotherapy since it is involved in an essential cellular function such as hemoglobin degradation during the parasite’s life cycle. However, despite their central role in the life cycle of the parasite, no commercial drug targeting Falcipain-2 has been developed to date. Prior efforts to develop peptide-based drugs against Plasmodium have been futile due to their susceptibility to being degraded by host enzymes. Objective:: Here we report computer-aided drug design of new nonpeptidic inhibitors against FP2, which are likely to be safe from degradation by host enzymes. Method: : We have virtually screened for the probable FP2 inhibitors from the PubChem database by submitting the wellequilibrated 3-D structure of FP2. Furthermore, virtual screenings and dockings were carried out using PyRx and Discovery Studio. Result: : We found 15 top-ranking molecules with carbaldehyde pharmacophore having a good fit with the target protein. Based on the C-Docker values, the top 4 hits (PubChem 44138738, PubChem 20983198, PubChem 20983081 and PubChem 28951461) for FP2 were identified. These four hits have been observed to bound to the active cleft of the protein. Moreover, their complexes were also found to be stable from the RMSD and Radius of Gyration analysis. Conclusion:: The selected compounds 2-(benzylamino)-8-methylquinoline-3-carbaldehyde (PubChem44138738), 6- bromo-2-(3,4-dihydro-1H-isoquinolin-2-yl)quinoline-3-carbaldehyde (PubChem 20983198), 2-(3,4-dihydro-1Hisoquinolin-2-yl)-6-ethylquinoline-3-carbaldehyde(PubChem20983081)and 2-[benzyl(methyl)amino]quinoline-3- carbaldehyde (PubChem 28951461) may be the starting point for further modification as a new type of nonpeptidic drug for malaria disease.

Malaria parasite plasmepsins: More than just plain old degradative pepsins

Plasmepsins are a group of diverse aspartic proteases in the malaria parasite Plasmodium. Their functions are strikingly multifaceted, ranging from hemoglobin degradation to secretory organelle protein processing for egress, invasion, and effector export. Some, particularly the digestive vacuole plasmepsins, have been extensively characterized, whereas others, such as the transmission-stage plasmepsins, are minimally understood. Some (e.g. plasmepsin V) have exquisite cleavage sequence specificity; others are fairly promiscuous. Some have canonical pepsin-like aspartic protease features, whereas others have unusual attributes, including the nepenthesin loop of plasmepsin V and a histidine in place of a catalytic aspartate in plasmepsin III. We have learned much about the functioning of these enzymes, but more remains to be discovered about their cellular roles and even their mechanisms of action. Their importance in many key aspects of parasite biology makes them intriguing targets for antimalarial chemotherapy. Further consideration of their characteristics suggests that some are more viable drug targets than others. Indeed, inhibitors of invasion and egress offer hope for a desperately needed new drug to combat this nefarious organism.

Recent Developments in Natural Product Inspired Synthetic 1,2,4- Trioxolanes (Ozonides): An Unusual Entry into Antimalarial Chemotherapy

According to WHO “World health statistics 2018”, malaria alongside acute respiratory infections and diarrhoea, is one of the major infectious disease causing children’s death in between the age of 1-5 years. Similarly, according to another report (2016) malaria accounts for approximately 3.14% of the total disease burden worldwide. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise due to the rapid spread of malaria parasites that are resistant to antimalarial drugs. Artemisinin (8), a major breakthrough in the antimalarial chemotherapy was isolated from the plant Artemisia annua in 1972. Its semi-synthetic derivatives such as artemether (9), arteether (10), and artesunic acid (11) are quite effective against multi-drug resistant malaria strains and are currently the drug of choice for the treatment of malaria. Inspite of exhibiting excellent antimalarial activity by artemisinin (8) and its derivatives, parallel programmes for the discovery of novel natural and synthetic peroxides were also the area of investigation of medicinal chemists all over the world. In these continuous efforts of extensive research, natural ozonide (1,2,4- trioxolane) was isolated from Adiantum monochlamys (Pteridaceae) and Oleandra wallichii (Davalliaceae) in 1976. These naturally occurring stable ozonides inspired chemists to investigate this novel class for antimalarial chemotherapy. The first identification of unusually stable synthetic antimalarial 1,2,4-trioxolanes was reported in 1992. Thus, an unusual entry of ozonides in the field of antimalarial chemotherapy had occurred in the early nineties. This review highlights the recent advancements and historical developments observed during the past 42 years (1976-2018) focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes (ozonides).

MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice

The deadliest complication of Plasmodium falciparum infection is cerebral malaria (CM), with a case fatality rate of 15 to 25% in African children despite effective antimalarial chemotherapy. No adjunctive treatments are yet available for this devastating disease. We previously reported that the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) rescued mice from experimental CM (ECM) when administered late in the infection, a time by which mice had already suffered blood–brain barrier (BBB) dysfunction, brain swelling, and hemorrhaging. Herein, we used longitudinal MR imaging to visualize brain pathology in ECM and the impact of a new DON prodrug, JHU-083, on disease progression in mice. We demonstrate in vivo the reversal of disease markers in symptomatic, infected mice following treatment, including the resolution of edema and BBB disruption, findings usually associated with a fatal outcome in children and adults with CM. Our results support the premise that JHU-083 is a potential adjunctive treatment that could rescue children and adults from fatal CM.