Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets

2001 ◽  
Vol 17 (11) ◽  
pp. 532-537 ◽  
Author(s):  
Graham H. Coombs ◽  
Daniel E. Goldberg ◽  
Michael Klemba ◽  
Colin Berry ◽  
John Kay ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Targets ◽  
Parasitic Protozoa ◽  
Aspartic Proteases

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

Transport processes in Plasmodium falciparum-infected erythrocytes: potential as new drug targets

2002 ◽  
Vol 32 (13) ◽  
pp. 1567-1573 ◽  
Author(s):  
Sanjeev Krishna ◽  
Ursula Eckstein-Ludwig ◽  
Thierry Joët ◽  
Anne-Catrin Uhlemann ◽  
Christophe Morin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Targets ◽  
Transport Processes ◽  
New Drug

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.

scholarly journals Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3721
Author(s):  
Ignasi Verdaguer ◽  
Camila Zafra ◽  
Marcell Crispim ◽  
Rodrigo Sussmann ◽  
Emília Kimura ◽  
...  
Keyword(s):  
Drug Targets ◽  
Shikimate Pathway ◽  
Mitochondrial Respiratory Chain ◽  
Side Chain ◽  
Head Group ◽  
Parasitic Protozoa ◽  
Amino Acid Degradation ◽  
Phylogenetic Origin ◽  
Metabolic Reactions ◽  
Vertebrate Hosts

Human parasitic protozoa cause a large number of diseases worldwide and, for some of these diseases, there are no effective treatments to date, and drug resistance has been observed. For these reasons, the discovery of new etiological treatments is necessary. In this sense, parasitic metabolic pathways that are absent in vertebrate hosts would be interesting research candidates for the identification of new drug targets. Most likely due to the protozoa variability, uncertain phylogenetic origin, endosymbiotic events, and evolutionary pressure for adaptation to adverse environments, a surprising variety of prenylquinones can be found within these organisms. These compounds are involved in essential metabolic reactions in organisms, for example, prevention of lipoperoxidation, participation in the mitochondrial respiratory chain or as enzymatic cofactors. This review will describe several prenylquinones that have been previously characterized in human pathogenic protozoa. Among all existing prenylquinones, this review is focused on ubiquinone, menaquinone, tocopherols, chlorobiumquinone, and thermoplasmaquinone. This review will also discuss the biosynthesis of prenylquinones, starting from the isoprenic side chains to the aromatic head group precursors. The isoprenic side chain biosynthesis maybe come from mevalonate or non-mevalonate pathways as well as leucine dependent pathways for isoprenoid biosynthesis. Finally, the isoprenic chains elongation and prenylquinone aromatic precursors origins from amino acid degradation or the shikimate pathway is reviewed. The phylogenetic distribution and what is known about the biological functions of these compounds among species will be described, as will the therapeutic strategies associated with prenylquinone metabolism in protozoan parasites.

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.

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