Enhanced anti-malarial efficacy of mefloquine delivered via cationic liposome in a murine model of experimental cerebral malaria.

Malaria is a longstanding global health challenge that continues to afflict over 90 countries located in tropical and subtropical regions of the globe. The rise of drug-resistant malarial parasites has curtailed the therapeutic efficacy of a number of once-effective anti-malarials, including mefloquine. In the present study, we have taken advantage of drug encapsulation approach to elevate the anti-malarial potential of mefloquine. Encouragingly, our findings unveil that liposomal formulations of mefloquine outperform equivalent doses of free mefloquine, both in laboratory cultures and in a murine model of malaria. Intriguingly, a cationic liposomal mefloquine formulation, administered at four successive doses of 3 mg/kg body weight, achieves complete resolution of cerebral malaria in the murine model while avoiding noticeable toxic repercussions. Altogether, our study furnishes pre-clinical validation for a therapeutic strategy that can remarkably enhance the drug efficacy, offering a revitalizing solution for failing anti-malarials.

Repurposing the Pathogen Box compounds for identification of potent anti-malarials against blood stages of Plasmodium falciparum with PfUCHL3 inhibitory activity.

Malaria has endured as a global epidemic since ages and its eradication poses an immense challenge due to the complex life cycle of the causative pathogen and its tolerance to a myriad of therapeutics. PfUCHL3, a member of the ubiquitin C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) is cardinal for parasite survival and emerges as a promising therapeutic target. In this quest, we employed a combination of computational and experimental approaches to identify PfUCHL3 inhibitors as novel anti-malarials. The Pathogen Box library was screened against the crystal structure of PfUCHL3 (PDB ID: 2WE6) and its human ortholog (PDB ID: 1XD3). Fifty molecules with better comparative score, bioavailability and druglikeliness were subjected to in-vitro enzyme inhibition assay and among them only two compounds effectively inhibited PfUCHL3 activity at micro molar concentrations. Both MMV676603 and MMV688704 exhibited anti-plasmodial activity by altering the parasite phenotype at late stages of the asexual life cycle and inducing the accumulation of polyubiquitinated substrates. In addition, both the compounds were non-toxic and portrayed high selectivity window for the parasite over mammalian cells. This is the first comprehensive study to demonstrate the anti-malarial efficacy of PfUCHL3 inhibitors and opens new avenues to exploit UCH family of DUBs as a promising target for the development of next generation anti-malaria therapy.

Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1.

The aberrant up-regulation of the oncogenic transcription factor Forkhead box M1 (FoxM1) is associated with tumor development, progression and metastasis in a myriad of carcinomas, thus establishing it as an attractive target for anticancer drug development. FoxM1 overexpression in hepatocellular carcinoma is reflective of tumor aggressiveness and recurrence, poor prognosis and low survival in patients. In our study, we have identified the antimalarial natural product, Artemisinin, to efficiently curb FoxM1 expression and activity in hepatic cancer cells, thereby exhibiting potential anticancer efficacy. Here, we demonstrated that Artemisinin considerably mitigates FoxM1 transcriptional activity by disrupting its interaction with the promoter region of its downstream targets, thereby suppressing the expression of numerous oncogenic drivers. Augmented level of FoxM1 is implicated in drug resistance of cancer cells, including hepatic tumor cells. Notably, FoxM1 overexpression rendered HCC cells poorly responsive to Artemisinin-mediated cytotoxicity while FoxM1 depletion in resistant liver cancer cells sensitized them to Artemisinin treatment, manifested in lower proliferative and growth index, drop in invasive potential and repressed expression of EMT markers with a concomitantly increased apoptosis. Moreover, Artemisinin, when used in combination with Thiostrepton, an established FoxM1 inhibitor, markedly reduced anchorage-independent growth and displayed more pronounced death in liver cancer cells. We found this effect to be evident even in the resistant HCC cells, thereby putting forth a novel combination therapy for resistant cancer patients. Altogether, our findings provide insight into the pivotal involvement of FoxM1 in the tumor suppressive activities of Artemisinin and shed light on the potential application of Artemisinin for improved therapeutic response, especially in resistant hepatic malignancies. Considering that Artemisinin compounds are in current clinical use with favorable safety profiles, the results from our study will potentiate its utility in juxtaposition with established FoxM1 inhibitors, promoting maximal therapeutic efficacy with minimal adverse effects in liver cancer patients.

Ionophores as Potent Anti-malarials: A Miracle in the Making.

Plasmodium has a complex life cycle that spans between mosquito and human. For survival and pathogenesis it banks upon dynamic alterations in ionic transport across organelle and plasma membrane. Being a fundamental contributor of crucial biological processes in parasite, ionic balance facilitates parasite invasion, augmentation and transmission. Past few decades have witnessed tremendous advancement in understanding the relevance of ionic transit in parasites. Perhaps, not surprisingly, disruption of ionic homeostasis was thought to be detrimental for parasite. Compounds like ionophores are known to facilitate ionic transport across membrane down their electrochemical gradient. Despite continuous effort, malaria treatment is still a challenge particularly due to the development of resistance among parasites against existing therapeutic options. However, repurposing the existing drugs can be advantageous over de novo drug development programs in terms of cost and associated risk factors. Ionophores, being used in coccidiosis have proven to be of significance in the treatment of experimental models of malaria. Several recent reports have highlighted the attractive potential of ionophores such as Monensin, Maduramicin, Valinomycin, etc., that can act against multiple stages of malarial parasite's life cycle. Improved variety of these molecules may help in mitigating the drug resistance problems as well. This review is an attempt to examine the relevant literature and provide insight into the mechanism and prospects of different classes of ionophores as promising anti-malarial potpourri.

Long circulatory liposomal maduramicin inhibits the growth of Plasmodium falciparum blood stages in culture and cures murine models of experimental malaria.

Malaria continues to be one of the deadliest infectious diseases and a global health menace. The emergence and spread of drug-resistant strains of malaria parasites have further made the process of disease management grimmer. Thus, there is an urgent need to identify promising antimalarial strategies that can target the blood stages as well as block parasite transmission. Maduramicin is one such ionophore selected out of a recent screen of gametocytocidal compounds that exhibit potent antiplasmodial activity. However, maduramicin's strong hydrophobic nature and associated toxicity restrict its application in chemotherapy. To alleviate this problem, we have developed a liposomal formulation loaded with the ionophore maduramicin for the treatment of chloroquine sensitive and resistant Plasmodium infections. Here, we show that maduramicin in PEGylated liposomal formulations displayed enhanced antiplasmodial activity in vitro compared to free maduramicin. Significantly, four consecutive doses of 1.5 mg kg-1 body weight of PEGylated maduramicin loaded lipid vesicles completely cured cerebral and chloroquine resistant murine models of malaria without any obvious toxic effects and suppressed the key inflammatory markers associated with the progression of the disease. PEGylated liposomal maduramicin also exhibited a prolonged plasma clearance rate, implying a greater chance of interaction and uptake by infected RBCs. Furthermore, we also provide evidence that the detrimental effect of liposomal maduramicin on parasite survival is mediated by increased ROS generation and subsequent perturbation of parasite mitochondrial membrane potential. This study presents the first report to demonstrate the potent antimalarial efficacy of maduramicin liposomes, a strategy that holds promise for the development of successful therapeutic intervention against malaria in humans.