Antimalarial Drugs as Inspiration for Herbicides

2020 ◽  
Vol 31 (5) ◽  
pp. 216-220
Author(s):  
Joshua S. Mylne ◽  
Keith A. Stubbs
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Development ◽  
Herbicide Resistance ◽  
Antimalarial Drug ◽  
Antimalarial Drugs ◽  
Malarial Parasite ◽  
Malaria Research ◽  
Close Relationship ◽  
Popular Subject ◽  
Drug Leads

In addition to good stewardship, the unabated rise in herbicide resistance and dearth of truly new herbicides demands that new molecules be found. Over 30 years ago, a chloroplast-like organelle was found in the malarial parasite Plasmodium falciparum and herbicides demonstrated a close relationship existed to plants. Recently this idea was turned on its head by exploiting the boom in malaria research to search for new herbicide chemistry and it provided interesting starting points for development. The merit of such an approach is underlined by tetflupyrolimet, the first truly novel herbicide in 30 years, and whose target has been a popular subject for antimalarial drug development for 15 years. Which other antimalarial targets, drugs and drug leads might reach across the parasite-plant divide to inspire new herbicides?

scholarly journals Plasmodium falciparum: new molecular targets with potential for antimalarial drug development

2009 ◽  
Vol 7 (9) ◽  
pp. 1087-1098 ◽  
Author(s):  
Donald L Gardiner ◽  
Tina S Skinner-Adams ◽  
Christopher L Brown ◽  
Katherine T Andrews ◽  
Colin M Stack ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Molecular Targets ◽  
New Molecular Targets

scholarly journals Comparison of Efficacies of Cysteine Protease Inhibitors against Five Strains of Plasmodium falciparum

2001 ◽  
Vol 45 (3) ◽  
pp. 949-951 ◽  
Author(s):  
Ajay Singh ◽  
Philip J. Rosenthal
Keyword(s):  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Cysteine Protease ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Antimalarial Drugs ◽  
Cross Resistance ◽  
Cysteine Protease Inhibitors ◽  
Antimalarial Agents ◽  
Parasite Strains

ABSTRACT Falcipain-2, a cysteine protease and essential hemoglobinase ofPlasmodium falciparum, is a potential antimalarial drug target. We compared the falcipain-2 sequences and sensitivities to cysteine protease inhibitors of five parasite strains that differ markedly in sensitivity to established antimalarial drugs. The sequence of falcipain-2 was highly conserved, and the sensitivities of all of the strains to falcipain-2 inhibitors were very similar. Thus, cross-resistance between cysteine protease inhibitors and other antimalarial agents is not expected in parasites that are now circulating and falcipain-2 remains a promising chemotherapeutic target.

scholarly journals Role ofPfmdr1inIn VitroPlasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

2014 ◽  
Vol 58 (12) ◽  
pp. 7032-7040 ◽  
Author(s):  
Nathalie Wurtz ◽  
Bécaye Fall ◽  
Aurélie Pascual ◽  
Mansour Fall ◽  
Eric Baret ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Antimalarial Drug ◽  
Antimalarial Drugs ◽  
Wild Type ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Increased Susceptibility

ABSTRACTThe involvement ofPfmdr1(Plasmodium falciparummultidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms inPfmdr1(N86Y, Y184F, S1034C, N1042D, and D1246Y) andPfcrt(K76T) andin vitroresponses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174Plasmodium falciparumisolates from Dakar, Senegal. ThePfmdr186Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. ThePfmdr186Y mutation was significantly associated with increased susceptibility to MDAQ (P= 0.0023), LMF (P= 0.0001), DHA (P= 0.0387), and MQ (P= 0.00002). The N86Y mutation was not associated with CQ (P= 0.214) or QN (P= 0.287) responses. ThePfmdr1184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P= 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). ThePfmdr186Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P= 0.0136), LMF (P= 0.0019), and MQ (P= 0.0001). The additionalPfmdr186Y mutation increased significantly thein vitrosusceptibility to MDAQ (P< 0.0001), LMF (P< 0.0001), MQ (P< 0.0001), and QN (P= 0.0026) in wild-typePfcrtK76 parasites. The additionalPfmdr186Y mutation significantly increased thein vitrosusceptibility to CQ (P= 0.0179) inPfcrt76T CQ-resistant parasites.

scholarly journals Evaluation of antimalarial prescription pattern and susceptibility of Plasmodium falciparum isolates in Kaduna, Nigeria

2020 ◽  
Vol 13 (7) ◽  
pp. 3398-3410
Author(s):  
O. Ifeoluwa Akanni ◽  
J.O. Ehinmidu ◽  
R.O. Bolaji
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Antimalarial Drug ◽  
Drug Prescription ◽  
Artemisinin Combination Therapy ◽  
Therapy Resistance ◽  
Antimalarial Drugs ◽  
In Vitro Susceptibility

Nigeria carries the highest burden of malaria in terms of morbidity and mortality. This is compounded by continuous resistance of Plasmodium falciparum to antimalarial drugs. This study was designed to evaluate the profile of malaria patients’ antimalarial drug prescription and in vitro susceptibility of P. falciparum isolates to commonly prescribed antimalarial drugs in Kaduna, Nigeria. Three years’ records of patients antimalarial drug prescriptions were collated (2013 to 2015) and the in vitro antimalarial agent susceptibility was determined for 28 clinical isolates using WHO Mark III microtest. Artemisinin-based combination therapy (ACT) was the most prescribed antimalarial for the period under review (92.3-93.7%). Among the ACTs, Artemether-lumefantrine was most prescribed. Of the 28 P. falciparum isolates evaluated, 3 (10.71%) were resistant to chloroquine with a median IC50 of 4.82μM (4.60-8.14μM), while five (17.86%) were resistant to mefloquine with a median IC50 of 25μM (10.3-41μM), 7(25.00%) to artemether with a median IC50 of 2.69μM (2.09-8.77μM), 9 (32.14%) to artesunate-mefloquine combination with a median IC50 of 9.0μM (7.98-35μM) and to artesunate, 11(39.29%) were resistant with a median IC50 of 2.4μM (1.56-5.65μM). This result shows a decline in resistance of P. falciparum to chloroquine compared to period prior to artemisinin-combination therapy as well as reduced susceptibility to artesunate and artemether. Further in vitro and in vivo monitoring will be required to inform antimalarial drug policy change.Keywords: Antimalarial, Artemisinin-combination therapy, resistance, susceptibility, microtest.

scholarly journals Multiple-Strain Malaria Infection and Its Impacts on Plasmodium falciparum Resistance to Antimalarial Therapy: A Mathematical Modelling Perspective

2019 ◽  
Vol 2019 ◽  
pp. 1-26
Author(s):  
Titus Okello Orwa ◽  
Rachel Waema Mbogo ◽  
Livingstone Serwadda Luboobi
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Infection ◽  
Antimalarial Drugs ◽  
Malarial Parasite ◽  
Parasite Resistance ◽  
Mortality And Morbidity ◽  
Development Of Resistance ◽  
Contour Plots ◽  
Dynamics And Control ◽  
And Control

The emergence of parasite resistance to antimalarial drugs has contributed significantly to global human mortality and morbidity due to malaria infection. The impacts of multiple-strain malarial parasite infection have further generated a lot of scientific interest. In this paper, we demonstrate, using the epidemiological model, the effects of parasite resistance and competition between the strains on the dynamics and control of Plasmodium falciparum malaria. The analysed model has a trivial equilibrium point which is locally asymptotically stable when the parasite’s effective reproduction number is less than unity. Using contour plots, we observed that the efficacy of antimalarial drugs used, the rate of development of resistance, and the rate of infection by merozoites are the most important parameters in the multiple-strain P. falciparum infection and control model. Although the drug-resistant strain is shown to be less fit, the presence of both strains in the human host has a huge impact on the cost and success of antimalarial treatment. To reduce the emergence of resistant strains, it is vital that only effective antimalarial drugs are administered to patients in hospitals, especially in malaria-endemic regions. Our results emphasize the call for regular and strict surveillance on the use and distribution of antimalarial drugs in health facilities in malaria-endemic countries.

scholarly journals Novel, Rapid, and Inexpensive Cell-Based Quantification of Antimalarial Drug Efficacy

2004 ◽  
Vol 48 (5) ◽  
pp. 1807-1810 ◽  
Author(s):  
Tyler N. Bennett ◽  
Michelle Paguio ◽  
Bojana Gligorijevic ◽  
Clement Seudieu ◽  
Andrew D. Kosar ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Discovery ◽  
Lactate Dehydrogenase ◽  
Dehydrogenase Activity ◽  
Antimalarial Drug ◽  
Drug Efficacy ◽  
Antimalarial Drugs ◽  
Sybr Green ◽  
Sybr Green I ◽  
Lactate Dehydrogenase Activity

ABSTRACT We report on the development of a new SYBR Green I-based plate assay for analyzing the activities of antimalarial drugs against intraerythrocytic Plasmodium falciparum. This assay is considerably faster, less labor-intensive, and less expensive than conventional radiotracer (e.g., [3H]hypoxanthine and [3H]ethanolamine)-based assays or P. falciparum lactate dehydrogenase activity-based assays. The assay significantly improves the pace at which antimalarial drug discovery efforts may proceed.

scholarly journals Re-refinement of Plasmodium falciparum orotidine 5′-monophosphate decarboxylase provides a clearer picture of an important malarial drug target

2018 ◽  
Vol 74 (10) ◽  
pp. 664-668 ◽  
Author(s):  
Walter R. P. Novak ◽  
Korbin H. J. West ◽  
Lucy M. D. Kirkman ◽  
Gabriel S. Brandt
Keyword(s):  
Public Health ◽  
Plasmodium Falciparum ◽  
Drug Design ◽  
Electron Density ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Antimalarial Drugs ◽  
Important Advance ◽  
Structure Based Drug Design ◽  
Monophosphate Decarboxylase

The development of antimalarial drugs remains a public health priority, and the orotidine 5′-monophosphate decarboxylase from Plasmodium falciparum (PfOMPDC) has great potential as a drug target. The crystallization of PfOMPDC with substrate bound represents an important advance for structure-based drug-design efforts [Tokuoka et al. (2008), J. Biochem. 143, 69–78]. The complex of the enzyme bound to the substrate OMP (PDB entry 2za1) would be of particular utility in this regard. However, re-refinement of this structure of the Michaelis complex shows that the bound ligand is the product rather than the substrate. Here, the re-refinement of a set of three structures, the apo enzyme and two versions of the product-bound form (PDB entries 2za1, 2za2 and 2za3), is reported. The improved geometry and fit of these structures to the observed electron density will enhance their utility in antimalarial drug design.

Novel inhibitors of the Plasmodium falciparum electron transport chain

Parasitology ◽  
2014 ◽  
Vol 141 (1) ◽  
pp. 50-65 ◽  
Author(s):  
P. A. STOCKS ◽  
V. BARTON ◽  
T. ANTOINE ◽  
G. A. BIAGINI ◽  
S. A. WARD ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Electron Transport ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Electron Transport Chain ◽  
Type Ii ◽  
Dihydroorotate Dehydrogenase ◽  
Cytochrome Bc ◽  
Transport Chain ◽  
Promising Area

SUMMARYDue to an increased need for new antimalarial chemotherapies that show potency against Plasmodium falciparum, researchers are targeting new processes within the parasite in an effort to circumvent or delay the onset of drug resistance. One such promising area for antimalarial drug development has been the parasite mitochondrial electron transport chain (ETC). Efforts have been focused on targeting key processes along the parasite ETC specifically the dihydroorotate dehydrogenase (DHOD) enzyme, the cytochrome bc1 enzyme and the NADH type II oxidoreductase (PfNDH2) pathway. This review summarizes the most recent efforts in antimalarial drug development reported in the literature and describes the evolution of these compounds.

scholarly journals Atovaquone Tolerance in Plasmodium falciparum Parasites Selected for High-Level Resistance to a Dihydroorotate Dehydrogenase Inhibitor

2014 ◽  
Vol 59 (1) ◽  
pp. 686-689 ◽  
Author(s):  
Jennifer L. Guler ◽  
John White ◽  
Margaret A. Phillips ◽  
Pradipsinh K. Rathod
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Development ◽  
Cross Talk ◽  
Antimalarial Drug ◽  
Pyrimidine Biosynthesis ◽  
Dihydroorotate Dehydrogenase ◽  
Development Programs ◽  
Genetic Cross ◽  
High Level ◽  
Level Resistance

ABSTRACTAtovaquone is a component of Malarone, a widely prescribed antimalarial combination, that targets malaria respiration. Here we show that parasites with high-level resistance to an inhibitor of dihydroorotate dehydrogenase demonstrate unexpected atovaquone tolerance. Fortunately, the tolerance is diminished with proguanil, the second partner in Malarone. It is important to understand such “genetic cross talk” between respiration and pyrimidine biosynthesis since many antimalarial drug development programs target these two seemingly independent pathways.

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