Novel antimalarial drug targets: hope for new antimalarial drugs

2009 ◽  
Vol 2 (5) ◽  
pp. 469-489 ◽  
Author(s):  
Athar Alam ◽  
Manish Goyal ◽  
Mohd Shameel Iqbal ◽  
Chinmay Pal ◽  
Sumanta Dey ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Drug Targets ◽  
Antimalarial Drugs

Antimalarial Drug Targets and Drugs Targeting Dolichol Metabolic Pathway of Plasmodium falciparum

2014 ◽  
Vol 15 (4) ◽  
pp. 374-409 ◽  
Author(s):  
Tabish Qidwai ◽  
Avantika Priya ◽  
Nihal Khan ◽  
Himanshu Tripathi ◽  
Feroz Khan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Metabolic Pathway ◽  
Antimalarial Drug ◽  
Drug Targets

scholarly journals Mammalian deubiquitinating enzyme inhibitors display in vitro and in vivo activity against malaria parasites and potentiate artemisinin action

2020 ◽  
Author(s):  
Nelson V. Simwela ◽  
Katie R. Hughes ◽  
Michael T. Rennie ◽  
Michael P. Barrett ◽  
Andrew P. Waters
Keyword(s):  
Anticancer Agents ◽  
Drug Targets ◽  
Reverse Genetics ◽  
Enzyme Inhibitors ◽  
Artemisinin Resistance ◽  
Drug Repurposing ◽  
Antimalarial Drugs ◽  
Malaria Parasites

AbstractCurrent malaria control efforts rely significantly on artemisinin combinational therapies which have played massive roles in alleviating the global burden of the disease. Emergence of resistance to artemisinins is therefore, not just alarming but requires immediate intervention points such as development of new antimalarial drugs or improvement of the current drugs through adjuvant or combination therapies. Artemisinin resistance is primarily conferred by Kelch13 propeller mutations which are phenotypically characterised by generalised growth quiescence, altered haemoglobin trafficking and downstream enhanced activity of the parasite stress pathways through the ubiquitin proteasome system (UPS). Previous work on artemisinin resistance selection in a rodent model of malaria, which we and others have recently validated using reverse genetics, has also shown that mutations in deubiquitinating enzymes, DUBs (upstream UPS component) modulates susceptibility of malaria parasites to both artemisinin and chloroquine. The UPS or upstream protein trafficking pathways have, therefore, been proposed to be not just potential drug targets, but also possible intervention points to overcome artemisinin resistance. Here we report the activity of small molecule inhibitors targeting mammalian DUBs in malaria parasites. We show that generic DUB inhibitors can block intraerythrocytic development of malaria parasites in vitro and possess antiparasitic activity in vivo and can be used in combination with additive effect. We also show that inhibition of these upstream components of the UPS can potentiate the activity of artemisinin in vitro as well as in vivo to the extent that ART resistance can be overcome. Combinations of DUB inhibitors anticipated to target different DUB activities and downstream 20s proteasome inhibitors are even more effective at improving the potency of artemisinins than either inhibitors alone providing proof that targeting multiple UPS activities simultaneously could be an attractive approach to overcoming artemisinin resistance. These data further validate the parasite UPS as a target to both enhance artemisinin action and potentially overcome resistance. Lastly, we confirm that DUB inhibitors can be developed into in vivo antimalarial drugs with promise for activity against all of human malaria and could thus further exploit their current pursuit as anticancer agents in rapid drug repurposing programs.Graphical abstract

scholarly journals A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

2014 ◽  
Vol 59 (1) ◽  
pp. 356-364 ◽  
Author(s):  
Wesley Wu ◽  
Zachary Herrera ◽  
Danny Ebert ◽  
Katie Baska ◽  
Seok H. Cho ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Targets ◽  
Specific Activity ◽  
Drug Candidate ◽  
Content Type ◽  
Chemical Rescue ◽  
Growth Inhibitory ◽  
Parasite Populations

ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

A proteomic glimpse into the effect of antimalarial drugs on Plasmodium falciparum proteome towards highlighting possible therapeutic targets

2020 ◽  
Author(s):  
Majid Dousti ◽  
Raúl Manzano-Román ◽  
Sajad Rashidi ◽  
Gholamreza Barzegar ◽  
Niloofar Bavarsad Ahmadpour ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Calcium Binding ◽  
Drug Targets ◽  
Thioredoxin Reductase ◽  
Resistance Mechanisms ◽  
Antimalarial Drugs ◽  
Effective Vaccine ◽  
Apical Membrane Antigen 1 ◽  
Clinic Management ◽  
Altered Proteins

Abstract There is no effective vaccine against malaria; therefore, chemotherapy is to date only choice to fight against this infectious disease. However, there are growing evidences of drug-resistance mechanisms in malaria treatments. Therefore, the identification of new drug targets is an urgent need for the clinic management of the disease. Proteomic approaches offer the chance of determining the effects of antimalarial drugs on the proteome of Plasmodium parasites. Accordingly, we here review the effects of antimalarial drugs on Plasmodium falciparum proteome pointing out the relevance of several proteins as possible drug targets in malaria treatment. In addition, some of the P. falciparum stage-specific altered proteins and parasite-host interactions might play important roles in pathogenicity, survival, invasion, and metabolic pathways and thus serve as potential source of drug targets. In this review, we have identified several proteins including thioredoxin reductase, helicases, peptidyl-prolyl cis-trans isomerase, endoplasmic reticulum-resident calcium-binding protein, choline/ethanolamine phosphotransferase, purine nucleoside phosphorylase, apical membrane antigen 1, glutamate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase, heat shock protein70x, knob-associated histidine-rich protein, and erythrocyte membrane protein 1 as promising antimalarial drugs targets. Overall, proteomic approaches are able to partially facilitate finding the possible drug targets. However, the integration of other ‘omics’ and specific pharmaceutical techniques with proteomics may increase the therapeutic properties of the critical proteins identified in P. falciparum proteome.

scholarly journals An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5182
Author(s):  
Chantalle Moolman ◽  
Rencia van der Sluis ◽  
Richard M. Beteck ◽  
Lesetja J. Legoabe
Keyword(s):  
Small Molecule ◽  
Antimalarial Drug ◽  
Kinase Inhibitors ◽  
Antimalarial Drugs ◽  
Next Generation ◽  
Antimalarial Drug Resistance ◽  
Cellular Processes ◽  
Antimalarial Agents ◽  
Molecule Inhibitor ◽  
Multiple Stages

Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.

scholarly journals Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria

2018 ◽  
Vol 115 (28) ◽  
pp. 7404-7409 ◽  
Author(s):  
Patrick Strangward ◽  
Michael J. Haley ◽  
Manuel G. Albornoz ◽  
Jack Barrington ◽  
Tovah Shaw ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Antimalarial Drug ◽  
Time Course ◽  
Treatment Success ◽  
Neurological Complication ◽  
Recovery Period ◽  
Antimalarial Drugs ◽  
Inflammasome Activation ◽  
Bioinformatics Analyses ◽  
Experimental Cerebral Malaria

Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1β production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1β release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33–NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM.

scholarly journals Re-Envisioning Anti-Apicomplexan Parasite Drug Discovery Approaches

2021 ◽  
Vol 11 ◽  
Author(s):  
Gabriel W. Rangel ◽  
Manuel Llinás
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Large Scale ◽  
Environmental Changes ◽  
Rapid Evolution ◽  
Antimalarial Drugs ◽  
Life Cycles ◽  
Drug Pressure ◽  
Apicomplexan Parasites ◽  
Resistance Evolution

Parasites of the phylum Apicomplexa impact humans in nearly all parts of the world, causing diseases including to toxoplasmosis, cryptosporidiosis, babesiosis, and malaria. Apicomplexan parasites have complex life cycles comprised of one or more stages characterized by rapid replication and biomass amplification, which enables accelerated evolutionary adaptation to environmental changes, including to drug pressure. The emergence of drug resistant pathogens is a major looming and/or active threat for current frontline chemotherapies, especially for widely used antimalarial drugs. In fact, resistant parasites have been reported against all modern antimalarial drugs within 15 years of clinical introduction, including the current frontline artemisinin-based combination therapies. Chemotherapeutics are a major tool in the public health arsenal for combatting the onset and spread of apicomplexan diseases. All currently approved antimalarial drugs have been discovered either through chemical modification of natural products or through large-scale screening of chemical libraries for parasite death phenotypes, and so far, none have been developed through a gene-to-drug pipeline. However, the limited duration of efficacy of these drugs in the field underscores the need for new and innovative approaches to discover drugs that can counter rapid resistance evolution. This review details both historical and current antimalarial drug discovery approaches. We also highlight new strategies that may be employed to discover resistance-resistant drug targets and chemotherapies in order to circumvent the rapid evolution of resistance in apicomplexan parasites.

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