ORCID Profile
0000-0002-6858-8547
Current Organisation
Nanyang Technological University
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Publisher: Springer Science and Business Media LLC
Date: 24-10-2015
Publisher: American Society for Microbiology
Date: 10-2015
DOI: 10.1128/AAC.00874-15
Abstract: The 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potent in vitro efficacies against Plasmodium falciparum , but susceptibility data for P. vivax are limited. The species- and stage-specific ex vivo activities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistant P. falciparum and P. vivax are prevalent. Both compounds were highly active against P. falciparum (median [range] 50% inhibitory concentration [IC 50 ]: NQ, 8.0 nM [2.6 to 71.8 nM] and MB, 1.6 nM [0.2 to 7.0 nM]) and P. vivax (NQ, 7.8 nM [1.5 to 34.2 nM] and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC 50 s in parasites exposed at the trophozoite stage than at the ring stage for NQ in P. falciparum (26.5 versus 5.1 nM, P = 0.021) and P. vivax (341.6 versus 6.5 nM, P = 0.021) and for MB in P. vivax (10.1 versus 1.6 nM, P = 0.010). The excellent ex vivo activities of NQ and MB against both P. falciparum and P. vivax highlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.
Publisher: American Chemical Society (ACS)
Date: 04-02-2019
DOI: 10.1021/ACS.JMEDCHEM.8B01799
Abstract: A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC
Publisher: Public Library of Science (PLoS)
Date: 04-10-2016
Publisher: American Chemical Society (ACS)
Date: 04-10-2016
Publisher: Public Library of Science (PLoS)
Date: 07-05-2020
Publisher: Elsevier BV
Date: 12-2021
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-07-2021
DOI: 10.1126/SCITRANSLMED.ABG6013
Abstract: We report an acylguanidine preclinical candidate with pharmacological features compatible with single low-dose malaria cure.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2014
DOI: 10.1038/NCOMMS6521
Abstract: The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na + regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na + homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na + homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-01-2019
DOI: 10.1126/SCITRANSLMED.AAU3174
Abstract: Mechanisms of action (MoAs) have been elusive for most antimalarial drugs in clinical use. Decreasing responsiveness to antimalarial treatments stresses the need for a better resolved understanding of their MoAs and associated resistance mechanisms. In the present work, we implemented the cellular thermal shift assay coupled with mass spectrometry (MS-CETSA) for drug target identification in
Publisher: American Society for Microbiology
Date: 09-2018
DOI: 10.1128/AAC.00012-18
Abstract: The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2021
DOI: 10.1101/2021.04.08.438947
Abstract: Despite their widespread use, our understanding of how many antiparasitic drugs work remains limited. We used mass-spectrometry based cellular thermal shift assay (MS-CETSA) to identify possible protein targets of several malaria drugs and drug candidates. We found that falcilysin (FLN) is a common target for several quinoline drugs including chloroquine and mefloquine, as well as drug candidates MK-4815, MMV000848 and MMV665806. At pH 7.5, these compounds all inhibit FLN proteolytic activity with IC 50 values ranging from 1.6 to 67.9 µM. Their interaction with FLN was systematically probed by isothermal titration calorimetry and X-ray crystallography, revealing a shared hydrophobic pocket in the catalytic chamber of the enzyme. Characterization of transgenic cell lines with depleted FLN expression demonstrated statistically significant increases in susceptibility towards chloroquine, mefloquine, MK-4815 and MMV000848. Taken together, our findings point to a multimodal mechanism of action for several commonly used anti-malaria drugs. Importantly, a common allosteric pocket of FLN appears amenable to inhibition, providing a structural basis to guide the development of novel drugs against malaria.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2017
DOI: 10.1038/NCOMMS15159
Abstract: K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro , is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2013
DOI: 10.1126/SCITRANSLMED.3005029
Abstract: ELQ-300, an investigational drug for treating and preventing malaria, shows potent transmission-blocking activity in rodent models of malaria.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2020
DOI: 10.1186/S12936-020-03436-W
Abstract: Sequencing technology advancements opened new opportunities to use transcriptomics for studying malaria pathology and epidemiology. Even though in recent years the study of whole parasite transcriptome proved to be essential in understanding parasite biology there is no compiled up-to-date reference protocol for the efficient generation of transcriptome data from growing number of s les. Here, a comprehensive methodology on how to preserve, extract, lify, and sequence full-length mRNA transcripts from Plasmodium -infected blood s les is presented that can be fully streamlined for high-throughput studies. The utility of various commercially available RNA-preserving reagents in a range of storage conditions was evaluated. Similarly, several RNA extraction protocols were compared and the one most suitable method for the extraction of high-quality total RNA from low-parasitaemia and low-volume blood s les was established. Furthermore, the criteria needed to evaluate the quality and integrity of Plasmodium RNA in the presence of human RNA was updated. Optimization of SMART-seq2 lification method to better suit AT-rich Plasmodium falciparum RNA s les allowed us to generate high-quality transcriptomes from as little as 10 ng of total RNA and a lower parasitaemia limit of 0.05%. Finally, a modified method for depletion of unwanted human haemoglobin transcripts using in vitro CRISPR-Cas9 treatment was designed, thus improving parasite transcriptome coverage in low parasitaemia s les. To prove the functionality of the pipeline for both laboratory and field strains, the highest 2-hour resolution RNA-seq transcriptome for P. falciparum 3D7 intraerythrocytic life cycle available to date was generated, and the entire protocol was applied to create the largest transcriptome data from Southeast Asian field isolates. Overall, the presented methodology is an inclusive pipeline for generation of good quality transcriptomic data from a erse range of Plasmodium -infected blood s les with varying parasitaemia and RNA inputs. The flexibility of this pipeline to be adapted to robotic handling will facilitate both small and large-scale future transcriptomic studies in the field of malaria.
Publisher: American Society for Microbiology
Date: 09-2015
DOI: 10.1128/AAC.01048-15
Abstract: Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo . Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum ( n = 41) and Plasmodium vivax ( n = 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum , the median 50% inhibitory concentrations (IC 50 s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ ( P 0.001 and P = 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM ( P 0.001 and P = 0.018, respectively). There was a significant correlation between IC 50 s of CQ and PL69 (Spearman's rank correlation coefficient [ r s ] = 0.727, P 0.001) and PL106 ( r s = 0.830, P 0.001) in P. vivax but not in P. falciparum . Both RCQs were equally active against the ring and trophozoite stages of P. falciparum , but in P. vivax , PL69 and PL106 showed less potent activity against trophozoite stages (median IC 50 s, 130.2 and 172.5 nM) compared to ring stages (median IC 50 s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax , suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species.
Publisher: American Society for Microbiology
Date: 08-2017
DOI: 10.1128/AAC.00355-17
Abstract: High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax . The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum , CQ 50% inhibitory concentrations (IC 50 s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs ( R 2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC 50 s was observed with any of the CQRRAs in P. vivax , even in those isolates with high chloroquine IC 50 s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: Public Library of Science (PLoS)
Date: 04-01-2013
Publisher: American Society for Microbiology
Date: 09-2014
DOI: 10.1128/AAC.02727-13
Abstract: Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo . Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
Publisher: American Society for Microbiology
Date: 2016
DOI: 10.1128/AAC.02207-15
Abstract: Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o ( pvcrt-o ) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5 P 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2016
Publisher: Public Library of Science (PLoS)
Date: 27-10-2016
Publisher: American Society for Microbiology
Date: 10-2012
DOI: 10.1128/AAC.00283-12
Abstract: The declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P. vivax malaria, comparative ex vivo antimalarial activity against Plasmodium isolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP). Ex vivo drug susceptibility was assessed in 46 field isolates (25 P. falciparum and 21 P. vivax ). The novel endoperoxide compounds exhibited potent ex vivo activity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC 50 s) in both species (median IC 50 s between 1.9 and 3.6 nM in P. falciparum and 0.7 and 4.6 nM in P. vivax ). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the two Plasmodium species: whereas their ex vivo activity correlated positively with CQ, PIP, AS, and DHA in P. falciparum , the same was not apparent in P. vivax . The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistant P. vivax . The high activity against drug-resistant strains of both Plasmodium species confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.
Publisher: American Society for Microbiology
Date: 11-2018
DOI: 10.1128/AAC.01941-18
Publisher: Springer Science and Business Media LLC
Date: 17-06-2015
DOI: 10.1038/NATURE14451
No related grants have been discovered for Grennady Wirjanata.