scholarly journals Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Tabish Qidwai ◽  
Farrukh Jamal ◽  
Mohd Y. Khan ◽  
Bechan Sharma
Keyword(s):  
Antimalarial Drug ◽  
Metabolic Pathways ◽  
Drug Target ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Biosynthetic Pathway ◽  
Comprehensive Analysis ◽  
Isoprenoid Biosynthesis ◽  
Biosynthesis Pathway ◽  
Novel Targets

Emergence of rapid drug resistance to existing antimalarial drugs inPlasmodium falciparumhas created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

scholarly journals Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Annie N. Cowell ◽  
Elizabeth A. Winzeler
Keyword(s):  
Drug Discovery ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Drug Targets ◽  
Trna Synthetase ◽  
Parasite Development ◽  
Major Advance ◽  
Liver Stage ◽  
Target Deconvolution ◽  
Novel Targets

Abstract A major advance in antimalarial drug discovery has been the shift towards cell-based phenotypic screening, with notable progress in the screening of compounds against the asexual blood stage, liver stage, and gametocytes. A primary method for drug target deconvolution in Plasmodium falciparum is in vitro evolution of compound-resistant parasites followed by whole-genome scans. Several of the most promising antimalarial drug targets, such as translation elongation factor 2 (eEF2) and phenylalanine tRNA synthetase (PheRS), have been identified or confirmed using this method. One drawback of this method is that if a mutated gene is uncharacterized, a substantial effort may be required to determine whether it is a drug target, a drug resistance gene, or if the mutation is merely a background mutation. Thus, the availability of high-throughput, functional genomic datasets can greatly assist with target deconvolution. Studies mapping genome-wide essentiality in P. falciparum or performing transcriptional profiling of the host and parasite during liver-stage infection with P. berghei have identified potentially druggable pathways. Advances in mapping the epigenomic regulation of the malaria parasite genome have also enabled the identification of key processes involved in parasite development. In addition, the examination of the host genome during infection has identified novel gene candidates associated with susceptibility to severe malaria. Here, we review recent studies that have used omics-based methods to identify novel targets for interventions against protozoan parasites, focusing on malaria, and we highlight the advantages and limitations of the approaches used. These approaches have also been extended to other protozoan pathogens, including Toxoplasma, Trypanosoma, and Leishmania spp., and these studies highlight how drug discovery efforts against these pathogens benefit from the utilization of diverse omics-based methods to identify promising drug targets.

scholarly journals Mosaic evolution of the phosphopantothenate biosynthesis pathway in bacteria and archaea

2020 ◽  
Author(s):  
Luc Thomès ◽  
Alain Lescure
Keyword(s):  
Metabolic Pathways ◽  
Biosynthetic Pathway ◽  
Coenzyme A ◽  
Symbiotic Bacteria ◽  
Dynamic Evolution ◽  
Biosynthesis Pathway ◽  
Protein Annotation ◽  
Picrophilus Torridus ◽  
Domains Of Life ◽  
Mosaic Evolution

Abstract Phosphopantothenate is a precursor to synthesis of Coenzyme A (CoA), a molecule essential to many metabolic pathways. Organisms of the archaeal phyla were shown to utilize a different phosphopantothenate biosynthetic pathway from the eukaryotic and bacterial one. In this study, we report that symbiotic bacteria from the group Candidatus poribacteria present enzymes of the archaeal pathway, namely pantoate kinase (PoK) and phosphopantothenate synthetase (PPS), mirroring what was demonstrated for Picrophilus torridus, an archaea partially utilizing the bacterial pathway. Our results support the ancient origin of the CoA pathway in the three domains of life, but also highlight its complex and dynamic evolution. Importantly, this study helps to improve protein annotation for this pathway in the Candidatus poribacteria group and other related organisms.

scholarly journals Bioinformatics of Thymidine metabolism in camels and Trypanosoma evansi: nucleoside deoxyribosyltransferase (NDRT) as a drug target

2020 ◽  
Author(s):  
Mahmoud Kandeel ◽  
Abdulla Al-Taher
Keyword(s):  
Metabolic Pathways ◽  
Drug Target ◽  
Drug Targets ◽  
3D Structure ◽  
Trypanosoma Evansi ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Sequence Comparisons ◽  
Phylogenetic Relations ◽  
Interesting Difference

Abstract Background Trypanosoma evansi (T. evansi), the causative agent for surra or camel trypanosomiasis, is characterized by the widest geographic distribution and infects the widest range of hosts among the known trypanosomes. The recent zoonotic importance and increasing reports of drug resistance necessitate the discovery of new drug targets. Drug discovery process entails finding an interesting difference between the host and the parasite. Results In this study, the thymidine metabolic pathways were compared in camel and T. evansi. Metabolic maps, protein sequence comparisons, domain and motifs contents analysis, phylogenetic relations and 3D structure models were used in comparisons. A unique difference in thymidine metabolism was at the level of recycling of thymidine which was performed by thymidine phosphorylase in camel, while this role is T. evansi was associated with nucleoside deoxyribosyltransferase (NDRT), which is a unique enzyme for the trypanosome and was absent in camel. Thymidine in T. evansi seems to be governed by thymine through NDRT. In contrast to camel, in which thymidine can be produced from thymidylate by the action of 5'-nucleotidase. Conclusions NDRT can be regarded as a drug target against T. evansi for its strict presence in the parasite but not in the host.

scholarly journals A specific non-bisphosphonate inhibitor of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites

2017 ◽  
Author(s):  
Jolyn E. Gisselberg ◽  
Zachary Herrera ◽  
Lindsey Orchard ◽  
Manuel Llinás ◽  
Ellen Yeh
Keyword(s):  
Plasmodium Falciparum ◽  
Physicochemical Properties ◽  
Small Molecule ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Drug Targets ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Malaria Parasites ◽  
Starting Point

SummaryIsoprenoid biosynthesis is essential for Plasmodium falciparum (malaria) parasites and contains multiple validated antimalarial drug targets, including a bifunctional farnesyl and geranylgeranyl diphosphate synthase (FPPS/GGPPS). We identified MMV019313 as an inhibitor of PfFPPS/GGPPS. Though PfFPPS/GGPPS is also inhibited by a class of bisphosphonate drugs, MMV019313 has significant advantages for antimalarial drug development. MMV019313 has superior physicochemical properties compared to charged bisphosphonates that have poor bioavailability and strong bone affinity. We also show that it is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes-of-inhibition against PfFPPS/GGPPS. Altogether MMV019313 is the first specific, non-bisphosphonate inhibitor of PfFPPS/GGPPS. Our findings uncover a new small molecule binding site in this important antimalarial drug target and provide a promising starting point for development of Plasmodium-specific FPPS/GGPPS inhibitors.

scholarly journals Analysis of metabolic pathways in mycobacteria to aid drug-target identification

2019 ◽  
Author(s):  
Bridget P. Bannerman ◽  
Sundeep C. Vedithi ◽  
Jorge Júlvez ◽  
Pedro Torres ◽  
Vaishali P. Waman ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Causative Agent ◽  
Metabolic Pathways ◽  
Drug Target ◽  
Drug Targets ◽  
Opportunistic Infections ◽  
Target Identification ◽  
Treatment Strategies ◽  
New Drugs ◽  
Drug Target Identification

AbstractThree related mycobacteria are the cause of widespread infections in man and are the focus of intense research and drug-discovery efforts in the face of growing antimicrobial resistance.Mycobacterium tuberculosis, the causative agent of tuberculosis, is currently one of the top ten causes of death in the world according to WHO;M.abscessus, a group of non-tuberculous mycobacteria causes lung infections and other opportunistic infections in humans; andM.leprae, the causative agent of leprosy, remains endemic in tropical countries. There is an urgent need to design alternatives to conventional treatment strategies, due to the increase in resistance to standard antibacterials. In this study, we present a comparative analysis of chokepoint and essentiality datasets that will provide insight into the development of new treatment regimes. We illustrate the key metabolic pathways shared between these three organisms and identify drug targets with a wide metabolic impact that are common to the three species. We demonstrate that 72% of the chokepoint enzymes are proteins essential toMycobacterium tuberculosis. We show also that 78% of the drug targets, prioritized based on their presence in multiple paths on the metabolic network, are present in pathways shared byM. tuberculosis, M.lepraeandM.abscessus, including biosynthesis of amino acids, carbohydrates, cell structures, fatty acid and lipid biosynthesis. A further 17% is found in the prioritised pathways shared betweenM. tuberculosisandM.abscessus. We have performed comparative structure modelling of potential drug targets identified using our analysis in order to assess druggability and demonstrate the importance of chokepoint analysis in terms of drug target identification.AUTHOR SUMMARYComputer simulation studies to design new drugs against mycobacteria

Targeting Protein Kinases in the Malaria Parasite: Update of an Antimalarial Drug Target

2012 ◽  
Vol 12 (5) ◽  
pp. 456-472 ◽  
Author(s):  
Veronica M. Zhang ◽  
Marina Chavchich ◽  
Norman C. Waters
Keyword(s):  
Protein Kinases ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Malaria Parasite

scholarly journals ATP2, the essential P4-ATPase of malaria parasites, catalyzes lipid-dependent ATP hydrolysis in complex with a Cdc50 β-subunit

2020 ◽  
Author(s):  
Anaïs Lamy ◽  
Ewerton Macarini-Bruzaferro ◽  
Alex Perálvarez-Marín ◽  
Marc le Maire ◽  
José Luis Vázquez-Ibar
Keyword(s):  
Antimalarial Drug ◽  
Drug Target ◽  
Malaria Parasite ◽  
Atp Hydrolysis ◽  
Head Groups ◽  
Phospholipid Distribution ◽  
Phosphatidylinositol 4 ◽  
P Type ◽  
Efficient Mechanisms

ABSTRACTEfficient mechanisms of lipid transport are indispensable for the Plasmodium malaria parasite along the different stages of its intracellular life-cycle. Gene targeting approaches have recently revealed the irreplaceable role of the Plasmodium-encoded type 4 P-type ATPases (P4-ATPases or lipid flippases), ATP2, together with its potential involvement as antimalarial drug target. In eukaryotic membranes, P4-ATPases assure their asymmetric phospholipid distribution by translocating phospholipids from the outer to the inner leaflet. As ATP2 is a yet putative transporter, in this work we have used a recombinantly-produced P. chabaudi ATP2, PcATP2, to gain insights into the function and structural organization of this essential transporter. Our work demonstrates that PcATP2 heterodimerizes with two of the three Plasmodium-encoded Cdc50 proteins: PcCdc50B and PcCdc50A, indispensable partners for most P4-ATPases. Moreover, the purified PcATP2/PcCdc50B complex catalyses ATP hydrolysis in the presence of phospholipids containing either phosphatidylserine, phosphatidylethanolamine or phosphatidylcholine head groups, and that this activity is upregulated by phosphatidylinositol 4-phosphate. Overall, our work provides the first study of the function and quaternary organization of ATP2, a promising antimalarial drug target candidate.

scholarly journals In Silico Knockout Screening of Plasmodium falciparum Reactions and Prediction of Novel Essential Reactions by Analysing the Metabolic Network

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Jelili Oyelade ◽  
Itunuoluwa Isewon ◽  
Efosa Uwoghiren ◽  
Olufemi Aromolaran ◽  
Olufunke Oladipupo
Keyword(s):  
Infectious Disease ◽  
Plasmodium Falciparum ◽  
Metabolic Network ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Drug Targets ◽  
New Drugs ◽  
Biological Evidence ◽  
Essential Reactions ◽  
Extensive List

Malaria is an infectious disease that affects close to half a million individuals every year and Plasmodium falciparum is a major cause of malaria. The treatment of this disease could be done effectively if the essential enzymes of this parasite are specifically targeted. Nevertheless, the development of the parasite in resisting existing drugs now makes discovering new drugs a core responsibility. In this study, a novel computational model that makes the prediction of new and validated antimalarial drug target cheaper, easier, and faster has been developed. We have identified new essential reactions as potential targets for drugs in the metabolic network of the parasite. Among the top seven (7) predicted essential reactions, four (4) have been previously identified in earlier studies with biological evidence and one (1) has been with computational evidence. The results from our study were compared with an extensive list of seventy-seven (77) essential reactions with biological evidence from a previous study. We present a list of thirty-one (31) potential candidates for drug targets in Plasmodium falciparum which includes twenty-four (24) new potential candidates for drug targets.

scholarly journals Identification of Plasmodium falciparum Mitochondrial Malate: Quinone Oxidoreductase Inhibitors from the Pathogen Box

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 471 ◽  
Author(s):  
Xinying Wang ◽  
Yukiko Miyazaki ◽  
Daniel Ken Inaoka ◽  
Endah Dwi Hartuti ◽  
Yoh-Ichi Watanabe ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Drug Targets ◽  
Tricarboxylic Acid Cycle ◽  
Drug Resistant ◽  
Quinone Oxidoreductase ◽  
Mitochondrial Inner Membrane ◽  
Transport Chain ◽  
Urgent Task

Malaria is one of the three major global health threats. Drug development for malaria, especially for its most dangerous form caused by Plasmodium falciparum, remains an urgent task due to the emerging drug-resistant parasites. Exploration of novel antimalarial drug targets identified a trifunctional enzyme, malate quinone oxidoreductase (MQO), located in the mitochondrial inner membrane of P. falciparum (PfMQO). PfMQO is involved in the pathways of mitochondrial electron transport chain, tricarboxylic acid cycle, and fumarate cycle. Recent studies have shown that MQO is essential for P. falciparum survival in asexual stage and for the development of experiment cerebral malaria in the murine parasite P. berghei, providing genetic validation of MQO as a drug target. However, chemical validation of MQO, as a target, remains unexplored. In this study, we used active recombinant protein rPfMQO overexpressed in bacterial membrane fractions to screen a total of 400 compounds from the Pathogen Box, released by Medicines for Malaria Venture. The screening identified seven hit compounds targeting rPfMQO with an IC50 of under 5 μM. We tested the activity of hit compounds against the growth of 3D7 wildtype strain of P. falciparum, among which four compounds showed an IC50 from low to sub-micromolar concentrations, suggesting that PfMQO is indeed a potential antimalarial drug target.

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