20 research outputs found
Streamlined and robust stage-specific profiling of gametocytocidal compounds against Plasmodium falciparum
Malaria elimination is dependent on the ability to target both the pathogenic and transmissible stages of the human malaria parasite, Plasmodium falciparum. These forms of the parasite are differentiated by unique developmental stages, each with their own biological mechanisms and processes. These individual stages therefore also respond differently to inhibitory compounds, and this complicates the discovery of multistage active antimalarial agents. The search for compounds with transmission-blocking activity has focused on screening for activity on mature gametocytes, with only limited descriptions available for the activity of such compounds on immature stage gametocytes. This therefore poses a gap in the profiling of antimalarial agents for pan-reactive, multistage activity to antimalarial leads. Here, we optimized an effective and robust strategy for the simple and cost-effective description of the stage-specific action of gametocytocidal antimalarial compounds.The South African Medical Research Council Strategic Health Innovation Partnership and the Department of Science and Innovation South African Research Chairs Initiative, administered through the South African National Research Foundation; a BMGF Grand Challenges Africa grant; the Medicines for Malaria Venture as Global Test center for stage-specific gametocytocidal assays.http://www.frontiersin.org/Cellular_and_Infection_Microbiologyhj2022BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC
Adapt or die : targeting unique transmission-stage biology for malaria elimination
Plasmodium parasites have a complex life cycle that includes development in the human
host as well as the Anopheles vector. Successful transmission of the parasite between its
host and vector therefore requires the parasite to balance its investments in asexual
replication and sexual reproduction, varying the frequency of sexual commitment to
persist within the human host and generate future opportunities for transmission. The
transmission window is extended further by the ability of stage V gametocytes to circulate
in peripheral blood for weeks, whereas immature stage I to IV gametocytes sequester in
the bone marrow and spleen until final maturation. Due to the low gametocyte numbers in
blood circulation and with the ease of targeting such life cycle bottlenecks, transmission
represents an efficient target for therapeutic intervention. The biological process of
Plasmodium transmission is a multistage, multifaceted process and the past decade
has seen a much deeper understanding of the molecular mechanisms and regulators
involved. Clearly, specific and divergent processes are used during transmission
compared to asexual proliferation, which both poses challenges but also opportunities
for discovery of transmission-blocking antimalarials. This review therefore presents an
update of our molecular understanding of gametocyte and gamete biology as well as the
status of transmission-blocking activities of current antimalarials and lead development
compounds. By defining the biological components associated with transmission,
considerations for the development of new transmission-blocking drugs to target such
untapped but unique biology is suggested as an important, main driver for transmissionblocking drug discovery.https://www.frontiersin.org/journals/cellular-and-infection-microbiologydm2022BiochemistryGeneticsMicrobiology and Plant PathologySchool of Health Systems and Public Health (SHSPH)UP Centre for Sustainable Malaria Control (UP CSMC
In vitro dual activity of Aloe marlothii roots and its chemical constituents against Plasmodium falciparum asexual and sexual stage parasites
Please abstract in the article.The Department of Science and Innovation (DSI) of South Africa; the South African Research Chairs Initiative of the DSI, administered through the South African National Research Foundation; the South African Medical Research Council; the University of Pretoria Postgraduate Research Support Bursary, South Africa and the LâOrĂ©al-UNESCO for Woman in Science grant.https://www.elsevier.com/locate/jethpharm2023-07-19hj2023BiochemistryChemistryGeneticsMicrobiology and Plant PathologySchool of Health Systems and Public Health (SHSPH)UP Centre for Sustainable Malaria Control (UP CSMC
The artemiside-artemisox-artemisone-m1 tetrad : efficacies against blood stage p. falciparum parasites, dmpk properties, and the case for artemiside
Because of the need to replace the current clinical artemisinins in artemisinin combination
therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the
thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin
(DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile
metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite
M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent
with artemiside and artemisone in vitro against asexual P. falciparum (Pf ) blood stage parasites (IC50
1.5â2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM
early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like
other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism
and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside,
artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax
value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold
higher than that attained following administration of artemisone alone. Given that efficacy of short
half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is
apparent that artemiside will be more active than artemisone in vivo, due to additive effects of
the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater
efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following
administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred
drug for incorporation into rational new artemisinin combination therapies.Supplementary Material 1: S1 Efficacy of artemisox, dose response curves against asexual, and gametocyte blood stage parasites: Figure S1aâe; S2 Efficacy of M1, dose response curves against asexual, and gametocyte blood stage parasites: Figure S2aâd; S3 Pharmacokinetics and metabolism, circulating concentrations of artemiside, artemisox, and artemisone: Table S3aâf, LC-MS/MS chromatograms of M1 Figure S3aâc; S4 In vitro efficacy dataâ previously published data for artemiside, artemisone, M1: Table S4aâc; S5 In vivo efficacy dataâ previously published data for artemiside, artemisone: Table S5; S6 Neurotoxicity dataâpreviously published neurotoxicity data for DHA, artesunate, artemiside, artemisone: Table S6.Supplementary Material 2: PDF copy of reference [37].The South African Medical Research Council (MRC) Flagship Project MALTB-Redox with funds from the National Treasury under its Economic Competitiveness and Support Package, a South African National Research Foundation (SA NRF) grant, and by a South African MRC Strategic Health Innovation Partnership (SHIP) grant, a South African MRC Collaborative Centre for Malaria Research grant and the Department of Science and Innovation and SA NRF South African Research Chairs Initiative (SARChI) Grant.https://www.mdpi.com/journal/pharmaceuticsam2022BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC
Activities of 11âazaartemisinin and Nâsulfonyl derivatives against asexual and transmissible malaria parasites
Dihydroartemisinin (DHA), either used in its own right or as the active drug generated inâ
vivo from the other artemisinins in current clinical useâartemether and artesunateâinduces quiescence in ringâstage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11âazaartemisinin 5 and selected Nâsulfonyl derivatives were screened against intraerythrocytic asexual stages of drugâsensitive Pf NF54 and drugâresistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC50 values 2000 toward asexual parasites. Overall, the readily accessible 11âazaartemisinin 5 and the sulfonyl derivatives 11 and 16 represent potential candidates for further development, in particular for transmission blocking of artemisininâresistant parasites.http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1860-71872018-12-19hj2018Biochemistr
Naphthylisoquinoline alkaloids, validated as hit multistage antiplasmodial natural products
The discovery and development of multistage antimalarial drugs targeting intra-erythrocytic asexual and sexual
Plasmodium falciparum parasites is of utmost importance to achieve the ambitious goal of malaria elimination.
Here, we report the validation of naphthylisoquinoline (NIQ) alkaloids and their synthetic analogues as multistage
active antimalarial drug candidates. A total of 30 compounds were tested, of which 17 exhibited IC50
values <1 ÎŒM against drug-sensitive P. falciparum parasites (NF54 strain); 15 of these retained activity against a
panel of drug-resistant strains. These compounds showed low in vitro cytotoxicity against HepG2 cells, with
selectivity indices of>10. The tested compounds showed activity in vitro against both early- and late-stage P.
falciparum gametocytes while blocking male gamete formation (> 70% inhibition of exflagellation at 2 ÎŒM).
Additionally, five selected compounds were found to have good solubility (â„170 ÎŒM in PBS at pH 6.5), while
metabolic stability towards human, mouse, and rat microsomes ranged from>90% to >7% after 30 min.
Dioncophylline C (2a) emerged as a front runner from the study, displaying activity against both asexual
parasites and gametocytes, a lack of cross-resistance to chloroquine, good solubility, and microsomal stability.
Overall, this is the first report on the multistage activity of NIQs and their synthetic analogues including gametocytocidal
and gametocidal effects induced by this class of compounds.We thank Dr. Raina Seupel, Dr. Jun Li, Dr. Christine Schies, Prof. Dr.
Dieudonné Tshitenge, and Dr. Sebastian Bischof for providing substances
tested in this study. The UP ISMC acknowledges the SAMRC as
Collaborating Centre for Malaria Research. This work was funded by
the South African Research Chairs Initiative of the Department of
Science and Technology, administered through the South African
National Research Foundation to LMB (UID 84627), and supported by
the SFB 630 âAgents against Infectious Diseasesâ funded by the
Deutsche Forschungsgesellschaft (DFG) to GB. ACCdS and TJE acknowledge
support of the National Institute of Allergy and Infectious
Diseases of the National Institutes of Health under grant number R01AI143521. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National
Institutes of Health.https://www.elsevier.com/locate/ijpddram2020BiochemistryChemistryGeneticsMicrobiology and Plant Patholog
Optimal 10-aminoartemisinins with potent transmission-blocking capabilities for new artemisinin combination therapiesâactivities against blood stage P. falciparum including PfKI3 C580Y mutants and liver stage P. berghei parasites
We have demonstrated previously that amino-artemisinins including artemiside and
artemisone in which an amino group replaces the oxygen-bearing substituents attached
to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether
and artesunate, display potent activities in vitro against the asexual blood stages
of Plasmodium falciparum (Pf ). In particular, the compounds are active against late
blood stage Pf gametocytes, and are strongly synergistic in combination with the
redox active drug methylene blue. In order to fortify the eventual selection of optimum
amino-artemisinins for development into new triple combination therapies also active
against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins
based on the easily accessible and inexpensive DHA-piperazine. The latter was
converted into alkyl- and aryl sulfonamides, ureas and amides. These derivatives were
screened together with the comparator drugs DHA and the hitherto most active
amino-artemisinins artemiside and artemisone against asexual and sexual blood stages
of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins
bearing aryl-urea and -amide groups are potently active against both asexual, and
late blood stage gametocytes (IC50 0.4-1.0 nM). Although the activities are superior to
those of artemiside (IC50 1.5 nM) and artemisone (IC50 42.4 nM), the latter are more
active against the liver stage Pb sporozoites (IC50 artemisone 28 nM). In addition, early
results indicate these compounds tend not to display reduced susceptibility against
parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside
and artemisone will enable the development of new combination therapies that by virtue
of the amino-artemisinin component itself will possess intrinsic transmission-blocking
capabilities and may be effective against artemisinin resistant falciparum malaria.Supplementary Table 1 | In vitro activities of selected amino-artemisinins against
liver stage P. berghei, dose response curves and cytotoxicities.Supplementary Material comprises experimental details for
synthesis and characterization data of the amino-artemisinins,
and dose response curves for the in vitro P. berghei sporozoite
stage efficacy assays recorded in Excel format in CDD Vault:
UCSD CDD_Vault_Export_RESULTS_KDE_03-25-2019.This work was funded by the South African Medical Research
Council (MRC) Flagship Project MALTB-Redox with funds
from National Treasury under its Economic Competitiveness
and Support Package to RH (MRC-RFA-UFSP-01-2013), the
South African MRC Strategic Health Innovation Partnership
(SHIP) grant, a South African MRC Collaborative Center
for Malaria Research grant and South African National
Research Foundation grants (UID 84627) to L-MB and to
RH (UIDs 90682 and 98934). EW was supported by grants
from the NIH (R01 AI090141-02), and Medicines for Malaria
Venture, Geneva.http://www.frontiersin.org/Chemistryam2020BiochemistryGeneticsMicrobiology and Plant Patholog
New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1 '-Biphenyl]-4-carboxamido)benzoic acid derivatives
Malaria elimination requires multipronged approaches, including
the application of antimalarial drugs able to block humanto-
mosquito transmission of malaria parasites. The transmissible
gametocytes of Plasmodium falciparum seem to be highly
sensitive towards epidrugs, particularly those targeting demethylation
of histone post-translational marks. Here, we report
exploration of compounds from a chemical library generated
during hit-to-lead optimization of inhibitors of the human
histone lysine demethylase, KDM4B. Derivatives of 2-([1,1â-
biphenyl]-4-carboxamido) benzoic acid, around either the
amide or a sulfonamide linker backbone (2-(arylcarboxamido)
benzoic acid, 2-carboxamide (arylsulfonamido)benzoic
acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide),
showed potent activity towards late-stage gametocytes (stage
IV/V) of P. falciparum, with the most potent compound reaching
single digit nanomolar activity. Structure-activity relationship
trends were evident and frontrunner compounds also displayed
microsomal stability and favourable solubility profiles. Simplified
synthetic routes support further derivatization of these
compounds for further development of these series as malaria
transmission-blocking agents.South African National Research Foundation;
BMGF Grand Challenges Africa;
South African Medical Research Council (SA MRC);
South Carolina SmartStateÂź Endowed Chair for Drug Discovery.https://chemistry-europe.onlinelibrary.wiley.com/journal/14397633am2023BiochemistryGeneticsMicrobiology and Plant PathologySchool of Health Systems and Public Health (SHSPH)UP Centre for Sustainable Malaria Control (UP CSMC
Antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains inhibit microtubule and hemozoin formation : structureâactivity relationship and in vivo oral efficacy studies
A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structureâactivity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 Ă 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.The University of Cape Town, South African Medical Research Council and South African Research Chairs Initiative of the Department of Science and Innovation, administered through the South African National Research Foundation (NRF) and a NRF Community of Practice on âEvaluating Malaria Control Interventionsâ.http://pubs.acs.org/loi/jmcmar2022-04-12hj2021BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC
Artemisone and artemiside - potent pan-reactive antimalarial agents that also synergize redox imbalance in P. falciparum transmissible gametocyte stages
The emergence of resistance towards artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, development of new artemisinins in combination with new drugs that impart activities towards both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular those of resistant parasites, are urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox-homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives towards the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes in the low nM range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displays notable synergism. These data suggest that modulation of redox-homeostasis likely is an important druggable process, particularly in gametocytes, and thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.The South African Medical Research Council (MRC) Flagship Project MALTB-Redox with funds from the National Treasury under its Economic Competitiveness and Support Package to Richard K. Haynes; a South African MRC Strategic Health Innovation Partnership (SHIP) grant, a South African MRC Collaborative Centre for Malaria Research grant, and a South African National Research Foundation grant (UID 84627) to Lyn-Marie Birkholtz; and South African National Research Foundation grants to Richard K. Haynes (UIDs 90682 and 98934). Donatella Taramelli and Sarah D'Alessandro acknowledge the support from the Global Health Program of the Bill & Melinda Gates Foundation (grant OPP1040394 to Donatella Taramelli, Pietro Alano coordinator, and COST Action CM1307).http://aac.asm.org2019-02-01hj2018Biochemistr