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1.
Bioorg Chem ; 149: 107510, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38833991

ABSTRACT

In the search for novel ligands with efficacy against various diseases, particularly parasitic diseases, molecular hybridization of organometallic units into biologically active scaffolds has been hailed as an appealing strategy in medicinal chemistry. The conjugation to organometallic fragments can be achieved by an appropriate linker or by directly coordinating the existing drugs to a metal. The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. We present the evolution of organometallic antimalarial agents over the last decade, focusing on the parent moiety's class and the type of organometallics involved. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases.


Subject(s)
Antimalarials , Organometallic Compounds , Antimalarials/chemistry , Antimalarials/pharmacology , Antimalarials/chemical synthesis , Humans , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Organometallic Compounds/chemical synthesis , Molecular Structure , Parasitic Sensitivity Tests , Malaria/drug therapy , Structure-Activity Relationship , Animals , Plasmodium falciparum/drug effects
2.
Phytochemistry ; 224: 114168, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38823569

ABSTRACT

Three previously undescribed highly modified lanostane triterpenoids, ganopyrone A, ganocolossusin I, and ganodermalactone Y, were isolated from the artificially cultivated fruiting bodies of the basidiomycete Ganoderma colossus TBRC-BCC 17711. Ganopyrone A possesses an unprecedented polycyclic carbon skeleton with an α-pyrone ring and C-18/C-23 bond. It showed antimalarial activity against Plasmodium falciparum K1 (multidrug-resistant strain) with an IC50 value of 7.8 µM (positive control: dihydroartemisinin, IC50 1.4 nM), while its cytotoxicity (Vero cells) was much weaker (IC50 103 µM).


Subject(s)
Antimalarials , Fruiting Bodies, Fungal , Ganoderma , Plasmodium falciparum , Triterpenes , Ganoderma/chemistry , Antimalarials/pharmacology , Antimalarials/chemistry , Antimalarials/isolation & purification , Plasmodium falciparum/drug effects , Fruiting Bodies, Fungal/chemistry , Triterpenes/pharmacology , Triterpenes/chemistry , Triterpenes/isolation & purification , Animals , Molecular Structure , Vero Cells , Chlorocebus aethiops , Lanosterol/analogs & derivatives , Lanosterol/pharmacology , Lanosterol/chemistry , Lanosterol/isolation & purification , Parasitic Sensitivity Tests , Structure-Activity Relationship , Dose-Response Relationship, Drug
3.
Int J Mol Sci ; 25(9)2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38731970

ABSTRACT

Malaria is a severe disease that presents a significant threat to human health. As resistance to current drugs continues to increase, there is an urgent need for new antimalarial medications. Aminoacyl-tRNA synthetases (aaRSs) represent promising targets for drug development. In this study, we identified Plasmodium falciparum tyrosyl-tRNA synthetase (PfTyrRS) as a potential target for antimalarial drug development through a comparative analysis of the amino acid sequences and three-dimensional structures of human and plasmodium TyrRS, with particular emphasis on differences in key amino acids at the aminoacylation site. A total of 2141 bioactive compounds were screened using a high-throughput thermal shift assay (TSA). Okanin, known as an inhibitor of LPS-induced TLR4 expression, exhibited potent inhibitory activity against PfTyrRS, while showing limited inhibition of human TyrRS. Furthermore, bio-layer interferometry (BLI) confirmed the high affinity of okanin for PfTyrRS. Molecular dynamics (MD) simulations highlighted the stable conformation of okanin within PfTyrRS and its sustained binding to the enzyme. A molecular docking analysis revealed that okanin binds to both the tyrosine and partial ATP binding sites of the enzyme, preventing substrate binding. In addition, the compound inhibited the production of Plasmodium falciparum in the blood stage and had little cytotoxicity. Thus, okanin is a promising lead compound for the treatment of malaria caused by P. falciparum.


Subject(s)
Antimalarials , Molecular Docking Simulation , Molecular Dynamics Simulation , Plasmodium falciparum , Tyrosine-tRNA Ligase , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Tyrosine-tRNA Ligase/antagonists & inhibitors , Tyrosine-tRNA Ligase/metabolism , Humans , Antimalarials/pharmacology , Antimalarials/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Binding Sites , Protein Binding , Animals , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology
4.
Front Cell Infect Microbiol ; 14: 1366563, 2024.
Article in English | MEDLINE | ID: mdl-38716192

ABSTRACT

Background: Routine surveillance for antimalarial drug resistance is critical to sustaining the efficacy of artemisinin-based Combination Therapies (ACTs). Plasmodium falciparum kelch-13 (Pfkelch-13) and non-Pfkelch-13 artemisinin (ART) resistance-associated mutations are uncommon in Africa. We investigated polymorphisms in Plasmodium falciparum actin-binding protein (Pfcoronin) associated with in vivo reduced sensitivity to ART in Nigeria. Methods: Fifty-two P. falciparum malaria subjects who met the inclusion criteria were followed up in a 28-day therapeutic efficacy study of artemether-lumefantrine in Lagos, Nigeria. Parasite detection was done by microscopy and molecular diagnostic approaches involving PCR amplification of genes for Pf18S rRNA, varATS, telomere-associated repetitive elements-2 (TARE-2). Pfcoronin and Pfkelch-13 genes were sequenced bi-directionally while clonality of infections was determined using 12 neutral P. falciparum microsatellite loci and msp2 analyses. Antimalarial drugs (sulfadoxine-pyrimethamine, amodiaquine, chloroquine and some quinolones) resistance variants (DHFR_51, DHFR_59, DHFR_108, DHFR_164, MDR1_86, MDR1_184, DHPS_581 and DHPS_613) were genotyped by high-resolution melting (HRM) analysis. Results: A total of 7 (26.92%) cases were identified either as early treatment failure, late parasitological failure or late clinical failure. Of the four post-treatment infections identified as recrudescence by msp2 genotypes, only one was classified as recrudescence by multilocus microsatellites genotyping. Microsatellite analysis revealed no significant difference in the mean allelic diversity, He, (P = 0.19, Mann-Whitney test). Allele sizes and frequency per locus implicated one isolate. Genetic analysis of this isolate identified two new Pfcoronin SNVs (I68G and L173F) in addition to the P76S earlier reported. Linkage-Disequilibrium as a standardized association index, IAS, between multiple P. falciparum loci revealed significant LD (IAS = 0.2865, P=0.02, Monte-Carlo simulation) around the neutral microsatellite loci. The pfdhfr/pfdhps/pfmdr1 drug resistance-associated haplotypes combinations, (108T/N/51I/164L/59R/581G/86Y/184F), were observed in two samples. Conclusion: Pfcoronin mutations identified in this study, with potential to impact parasite clearance, may guide investigations on emerging ART tolerance in Nigeria, and West African endemic countries.


Subject(s)
Antimalarials , Artemisinins , Drug Resistance , Malaria, Falciparum , Microfilament Proteins , Plasmodium falciparum , Adult , Female , Humans , Male , Antimalarials/pharmacology , Antimalarials/therapeutic use , Artemether, Lumefantrine Drug Combination/therapeutic use , Artemisinins/pharmacology , Artemisinins/therapeutic use , Drug Combinations , Drug Resistance/genetics , Genotype , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Microfilament Proteins/genetics , Microsatellite Repeats/genetics , Mutation , Nigeria , Plasmodium falciparum/genetics , Plasmodium falciparum/drug effects , Polymorphism, Genetic , Protozoan Proteins/genetics , Recurrence
5.
Nat Rev Drug Discov ; 23(6): 461-479, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38750260

ABSTRACT

Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human immunodeficiency virus (HIV) infection and tuberculosis. Therefore, there is an urgent need to develop novel drugs and treatment protocols capable of reducing the emergence of resistance and combating it when it does occur. In this Review, we present an overview of the status and underlying molecular mechanisms of drug resistance in these three diseases. We also discuss current strategies to address resistance during the research and development of next-generation therapies. These strategies vary depending on the infectious agent and the array of resistance mechanisms involved. Furthermore, we explore the potential for cross-fertilization of knowledge and technology among these diseases to create innovative approaches for minimizing drug resistance and advancing the discovery and development of new anti-infective treatments. In conclusion, we advocate for the implementation of well-defined strategies to effectively mitigate and manage resistance in all interventions against infectious diseases.


Subject(s)
HIV Infections , Malaria , Tuberculosis , Humans , Malaria/drug therapy , HIV Infections/drug therapy , Tuberculosis/drug therapy , Antitubercular Agents/therapeutic use , Antitubercular Agents/pharmacology , Animals , Antimalarials/therapeutic use , Antimalarials/pharmacology
6.
J Mol Model ; 30(6): 181, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38780838

ABSTRACT

CONTEXT: Malaria remains a significant global health challenge with emerging resistance to current treatments. Plasmodium falciparum glutathione reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarials and dual drugs combining aminoquinoline derivatives with GR inhibitors, which reveal promising interactions between PfGR and studied drugs. The naphthoquinone Atovaquone demonstrated particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity, suggesting their efficacy in inhibiting PfGR, where the aliphatic ester bond (linker) is essential for effective binding with the enzyme's active site. Overall, this research provides important insights into the interactions between antimalarial agents and PfGR and encourages further exploration of its role in the mechanisms of action of antimalarials, including dual drugs, to enhance antiparasitic efficacy. METHODS: The drugs were tested as PfGR potential inhibitors via molecular docking on AutoDock 4, which was performed based on the preoptimized structures in HF/3-21G-PCM level of theory on ORCA 5. Drug-receptor systems with the most promising binding affinities were then studied with a molecular dynamic's simulation on AMBER 16. The molecular dynamics simulations were performed with a 100 ns NPT ensemble employing GAFF2 forcefield in the temperature of 310 K, integration time step of 2 fs, and non-bond cutoff distance of 6.0 Å.


Subject(s)
Antimalarials , Glutathione Reductase , Molecular Docking Simulation , Molecular Dynamics Simulation , Plasmodium falciparum , Antimalarials/chemistry , Antimalarials/pharmacology , Plasmodium falciparum/enzymology , Plasmodium falciparum/drug effects , Glutathione Reductase/antagonists & inhibitors , Glutathione Reductase/chemistry , Glutathione Reductase/metabolism , Protein Binding , Catalytic Domain , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans
7.
Bioorg Med Chem Lett ; 108: 129800, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38763480

ABSTRACT

In a quest to discover new antimalarial and antitubercular drugs, we have designed and synthesized a series of novel triazole-quinazolinone hybrids. The in vitro screening of the triazole-quinazolinone hybrid entities against the plasmodium species P. falciparum offered potent antimalarial molecules 6c, 6d, 6f, 6g, 6j & 6k owing comparable activity to the reference drugs. Furthermore, the target compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv strain. Among the screened compounds, 6c, 6d and 6l were found to be the most active molecules with a MIC values of 19.57-40.68 µM. The cytotoxicity of the most active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed. The computational study including drug likeness and ADMET profiling, DFT, and molecular docking study was done to explore the features of target molecules. The compounds 6a, 6g, and 6k exhibited highest binding affinity of -10.3 kcal/mol with docked molecular targets from M. tuberculosis. Molecular docking study indicates that all the molecules are binding to the falcipain 2 protease (PDB: 6SSZ) of the P. falciparum. Our findings indicated that these new triazole-quinazolinone hybrids may be considered hit molecules for further optimization studies.


Subject(s)
Antimalarials , Antitubercular Agents , Drug Design , Microbial Sensitivity Tests , Molecular Docking Simulation , Mycobacterium tuberculosis , Plasmodium falciparum , Quinazolinones , Triazoles , Antitubercular Agents/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antimalarials/pharmacology , Antimalarials/chemical synthesis , Antimalarials/chemistry , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Mycobacterium tuberculosis/drug effects , Plasmodium falciparum/drug effects , Quinazolinones/chemistry , Quinazolinones/pharmacology , Quinazolinones/chemical synthesis , Mice , Structure-Activity Relationship , Animals , Molecular Structure , Dose-Response Relationship, Drug , RAW 264.7 Cells
8.
Environ Toxicol Pharmacol ; 108: 104465, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38734396

ABSTRACT

Malaria represents the greatest global health burden among all parasitic diseases, with drug resistance representing the primary obstacle to control efforts. Sodium metavanadate (NaVO3) exhibits antimalarial activity against the Plasmodium yoelii yoelii (Pyy), yet its precise antimalarial mechanism remains elusive. This study aimed to assess the antimalarial potential of NaVO3, evaluate its genotoxicity, and determine the production of reactive oxygen and nitrogen species (ROS/RNS) in Pyy. CD-1 mice were infected and divided into two groups: one treated orally with NaVO3 (10 mg/kg/day for 4 days) and the other untreated. A 50% decrease in parasitemia was observed in treated mice. All experimental days demonstrated DNA damage in exposed parasites, along with an increase in ROS and RNS on the fifth day, suggesting a possible parasitostatic effect. The results indicate that DNA is a target of NaVO3, but further studies are necessary to fully elucidate the mechanisms underlying its antimalarial activity.


Subject(s)
Antimalarials , DNA Damage , Plasmodium yoelii , Reactive Nitrogen Species , Reactive Oxygen Species , Vanadates , Animals , Plasmodium yoelii/drug effects , DNA Damage/drug effects , Mice , Reactive Oxygen Species/metabolism , Antimalarials/toxicity , Antimalarials/pharmacology , Reactive Nitrogen Species/metabolism , Vanadates/toxicity , Vanadates/pharmacology , Malaria/drug therapy , Male , Parasitemia , Female
9.
mBio ; 15(6): e0198123, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38700363

ABSTRACT

Reduced susceptibility to ART, the first-line treatment against malaria, is common in South East Asia (SEA). It is associated with point mutations, mostly in kelch13 (k13) but also in other genes, like ubp1. K13 and its compartment neighbors (KICs), including UBP1, are involved in endocytosis of host cell cytosol. We tested 135 mutations in KICs but none conferred ART resistance. Double mutations of k13C580Y with k13R539T or k13C580Y with ubp1R3138H, did also not increase resistance. In contrast, k13C580Y parasites subjected to consecutive RSAs did, but the k13 sequence was not altered. Using isogenic parasites with different k13 mutations, we found correlations between K13 protein amount, resistance, and fitness cost. Titration of K13 and KIC7 indicated that the cellular levels of these proteins determined resistance through the rate of endocytosis. While fitness cost of k13 mutations correlated with ART resistance, ubp1R3138H caused a disproportionately higher fitness cost. IMPORTANCE: Parasites with lowered sensitivity to artemisinin-based drugs are becoming widespread. However, even in these "resistant" parasites not all parasites survive treatment. We found that the proportion of surviving parasites correlates with the fitness cost of resistance-inducing mutations which might indicate that the growth disadvantages prevents resistance levels where all parasites survive treatment. We also found that combining two common resistance mutations did not increase resistance levels. However, selection through repeated ART-exposure did, even-though the known resistance genes, including k13, were not further altered, suggesting other causes of increased resistance. We also observed a disproportionally high fitness cost of a resistance mutation in resistance gene ubp1. Such high fitness costs may explain why mutations in ubp1 and other genes functioning in the same pathway as k13 are rare. This highlights that k13 mutations are unique in their ability to cause resistance at a comparably low fitness cost.


Subject(s)
Antimalarials , Artemisinins , Drug Resistance , Plasmodium falciparum , Protozoan Proteins , Plasmodium falciparum/genetics , Plasmodium falciparum/drug effects , Drug Resistance/genetics , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Antimalarials/pharmacology , Artemisinins/pharmacology , Mutation , Humans , Malaria, Falciparum/parasitology , Genetic Fitness , Asia, Southeastern , Endocytosis
10.
mBio ; 15(6): e0237723, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38709067

ABSTRACT

Plasmodium falciparum, the deadly protozoan parasite responsible for malaria, has a tightly regulated gene expression profile closely linked to its intraerythrocytic development cycle. Epigenetic modifiers of the histone acetylation code have been identified as key regulators of the parasite's transcriptome but require further investigation. In this study, we map the genomic distribution of Plasmodium falciparum histone deacetylase 1 (PfHDAC1) across the erythrocytic asexual development cycle and find it has a dynamic occupancy over a wide array of developmentally relevant genes. Overexpression of PfHDAC1 results in a progressive increment in parasite load over consecutive rounds of the asexual infection cycle and is associated with enhanced gene expression of multiple families of host cell invasion factors (merozoite surface proteins, rhoptry proteins, etc.) and with increased merozoite invasion efficiency. With the use of class-specific inhibitors, we demonstrate that PfHDAC1 activity in parasites is crucial for timely intraerythrocytic development. Interestingly, overexpression of PfHDAC1 results in decreased sensitivity to frontline-drug dihydroartemisinin in parasites. Furthermore, we identify that artemisinin exposure can interfere with PfHDAC1 abundance and chromatin occupancy, resulting in enrichment over genes implicated in response/resistance to artemisinin. Finally, we identify that dihydroartemisinin exposure can interrupt the in vitro catalytic deacetylase activity and post-translational phosphorylation of PfHDAC1, aspects that are crucial for its genomic function. Collectively, our results demonstrate PfHDAC1 to be a regulator of critical functions in asexual parasite development and host invasion, which is responsive to artemisinin exposure stress and deterministic of resistance to it. IMPORTANCE: Malaria is a major public health problem, with the parasite Plasmodium falciparum causing most of the malaria-associated mortality. It is spread by the bite of infected mosquitoes and results in symptoms such as cyclic fever, chills, and headache. However, if left untreated, it can quickly progress to a more severe and life-threatening form. The World Health Organization currently recommends the use of artemisinin combination therapy, and it has worked as a gold standard for many years. Unfortunately, certain countries in southeast Asia and Africa, burdened with a high prevalence of malaria, have reported cases of drug-resistant infections. One of the major problems in controlling malaria is the emergence of artemisinin resistance. Population genomic studies have identified mutations in the Kelch13 gene as a molecular marker for artemisinin resistance. However, several reports thereafter indicated that Kelch13 is not the main mediator but rather hinted at transcriptional deregulation as a major determinant of drug resistance. Earlier, we identified PfGCN5 as a global regulator of stress-responsive genes, which are known to play a central role in artemisinin resistance generation. In this study, we have identified PfHDAC1, a histone deacetylase as a cell cycle regulator, playing an important role in artemisinin resistance generation. Taken together, our study identified key transcriptional regulators that play an important role in artemisinin resistance generation.


Subject(s)
Antimalarials , Artemisinins , Histone Deacetylase 1 , Plasmodium falciparum , Plasmodium falciparum/genetics , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Artemisinins/pharmacology , Antimalarials/pharmacology , Histone Deacetylase 1/genetics , Histone Deacetylase 1/metabolism , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Humans , Erythrocytes/parasitology , Malaria, Falciparum/parasitology , Reproduction, Asexual/genetics
11.
mBio ; 15(6): e0096624, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38717141

ABSTRACT

To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound MMV1557817 is a selective, nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. MMV1557817 can kill sexual-stage P. falciparum, is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials. MMV1557817-resistant P. falciparum exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these results confirm MMV1557817 as a lead compound for further drug development and highlights the potential of dual inhibition of M1 and M17 as an effective multi-species drug-targeting strategy.IMPORTANCEEach year, malaria infects approximately 240 million people and causes over 600,000 deaths, mostly in children under 5 years of age. For the past decade, artemisinin-based combination therapies have been recommended by the World Health Organization as the standard malaria treatment worldwide. Their widespread use has led to the development of artemisinin resistance in the form of delayed parasite clearance, alongside the rise of partner drug resistance. There is an urgent need to develop and deploy new antimalarial agents with novel targets and mechanisms of action. Here, we report a new and potent antimalarial compound, known as MMV1557817, and show that it targets multiple stages of the malaria parasite lifecycle, is active in a preliminary mouse malaria model, and has a novel mechanism of action. Excitingly, resistance to MMV15578117 appears to be self-limiting, suggesting that development of the compound may provide a new class of antimalarial.


Subject(s)
Aminopeptidases , Antimalarials , Plasmodium falciparum , Plasmodium vivax , Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Animals , Mice , Plasmodium vivax/drug effects , Plasmodium vivax/enzymology , Aminopeptidases/antagonists & inhibitors , Aminopeptidases/metabolism , Drug Resistance , Humans , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/metabolism , Protozoan Proteins/genetics , Female
12.
Proc Natl Acad Sci U S A ; 121(21): e2322923121, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38739798

ABSTRACT

The ubiquitin-proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, including Plasmodium falciparum, the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin-proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disrupt P. falciparum growth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein-protein interactions within the Plasmodium ubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of antimalarial therapeutics.


Subject(s)
Peptides , Plasmodium falciparum , Protozoan Proteins , Ubiquitin Thiolesterase , Plasmodium falciparum/enzymology , Plasmodium falciparum/metabolism , Plasmodium falciparum/drug effects , Ubiquitin Thiolesterase/metabolism , Ubiquitin Thiolesterase/antagonists & inhibitors , Ubiquitin Thiolesterase/genetics , Humans , Peptides/chemistry , Peptides/metabolism , Peptides/pharmacology , Protozoan Proteins/metabolism , Protozoan Proteins/chemistry , Protozoan Proteins/genetics , Protozoan Proteins/antagonists & inhibitors , Antimalarials/pharmacology , Antimalarials/chemistry , Ubiquitin/metabolism , Malaria, Falciparum/parasitology , Malaria, Falciparum/drug therapy
13.
J Inorg Biochem ; 257: 112614, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38781850

ABSTRACT

Ruthenium complexes containing triphenylphosphine diamide ligands were prepared, characterized, and tested for their biological activity against various cancer cell lines and the malaria parasite, Plasmodium falciparum. The effect of M (mono-substituted) and B (bis-substituted) complexes on the human cervical carcinoma (HeLa) cell line was investigated using the MTT assay. Five (B2, B3, B5, B6, and B13) of the 24 synthesized ruthenium complexes showed significant effects with IC50 values ranging between 0.3 and 2.3 µM. Evaluation of the potential biomolecular targets of B2 and B13 by fluorescence spectroscopy revealed relevant interactions with BSA and only a weak affinity for ctDNA. Complexes M2, B2, M13 and B13 were selected for further biological characterization. Their effect on the viability of two ovarian cancer cell lines was compared to normal cell lines, denoting their selectivity. Upon treatment of four different drug-resistant gynaecological cancer cell lines, differing in their multidrug-resistant phenotypes, the efficacy of the bis-substituted complexes was shown to be greater than their mono-substituted counterparts. The non-MDR cells are sensitive to all the tested complexes, compared to MDR cells which are less sensitive. Upon investigation of complexes M2, M13, B2, and B13 against sensitive and multidrug-resistant parasite strains of P. falciparum, the bis-substituted complexes were again shown to be the most potent, with submicromolar activity against both strains. Furthermore, the resistance indexes for the complexes were approximately equal to 1, which is at least 5-fold lower than chloroquine diphosphate, suggesting the ability of these complexes to retain their activity in resistant forms of the parasite.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Drug Resistance, Neoplasm , Plasmodium falciparum , Ruthenium , Humans , Plasmodium falciparum/drug effects , Ruthenium/chemistry , Ruthenium/pharmacology , Drug Resistance, Neoplasm/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antimalarials/pharmacology , Antimalarials/chemistry , Cell Line, Tumor , Drug Resistance, Multiple/drug effects , Cell Survival/drug effects , HeLa Cells , Animals , Organometallic Compounds/pharmacology , Organometallic Compounds/chemistry , Organometallic Compounds/chemical synthesis , Female
14.
BMC Res Notes ; 17(1): 129, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38725016

ABSTRACT

OBJECTIVES: The study evaluated sub-microscopic malaria infections in pregnancy using two malaria Rapid Diagnostic Tests (mRDTs), microscopy and RT-PCR and characterized Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and Plasmodium falciparum dihydropteroate synthase (Pfdhps) drug resistant markers in positive samples. METHODS: This was a cross sectional survey of 121 pregnant women. Participants were finger pricked, blood drops were collected for rapid diagnosis with P. falciparum histidine-rich protein 11 rapid diagnostic test kit and the ultra-sensitive Alere Pf malaria RDT, Blood smears for microscopy and dried blood spots on Whatman filter paper for molecular analysis were made. Real time PCR targeting the var acidic terminal sequence (varATS) gene of P. falciparum was carried out on a CFX 96 real time system thermocycler (BioRad) in discriminating malaria infections. For each run, laboratory strain of P. falciparum 3D7 and nuclease free water were used as positive and negative controls respectively. Additionally, High resolution melt analyses was employed for genotyping of the different drug resistance markers. RESULTS: Out of one hundred and twenty-one pregnant women sampled, the SD Bioline™ Malaria Ag P.f HRP2-based malaria rapid diagnostic test (mRDT) detected eight (0.06%) cases, the ultra-sensitive Alere™ malaria Ag P.f rapid diagnostic test mRDT had similar outcome in the same samples as detected by the HRP2-based mRDT. Microscopy and RT-PCR confirmed four out of the eight infections detected by both rapid diagnostic tests as true positive and RT-PCR further detected three false negative samples by the two mRDTs providing a sub-microscopic malaria prevalence of 3.3%. Single nucleotide polymorphism in Pfdhps gene associated with sulphadoxine resistance revealed the presence of S613 mutant genotypes in three of the seven positive isolates and isolates with mixed wild/mutant genotype at codon A613S. Furthermore, four mixed genotypes at the A581G codon were also recorded while the other Pfdhps codons (A436G, A437G and K540E) showed the presence of wild type alleles. In the Pfdhfr gene, there were mutations in 28.6%, 28.6%, and 85.7% at the I51, R59 and N108 codons respectively. Mixed wild and mutant type genotypes were also observed in 28.6% each of the N51I, and C59R codons. For the Pfcrt, two haplotypes CVMNK and CVIET were observed. The SVMNT was altogether absent. Triple mutant CVIET 1(14.3%) and triple mutant + wild genotype CVIET + CVMNK 1(14.3%) were observed. The Pfmdr1 haplotypes were single mutants YYND 1(14.3%); NFND 1(14.3%) and double mutants YFND 4(57.1%); YYDD 1(14.3%).


Subject(s)
Malaria, Falciparum , Plasmodium falciparum , Polymorphism, Single Nucleotide , Female , Humans , Malaria, Falciparum/parasitology , Malaria, Falciparum/diagnosis , Malaria, Falciparum/epidemiology , Pregnancy , Plasmodium falciparum/genetics , Plasmodium falciparum/drug effects , Adult , Cross-Sectional Studies , Polymorphism, Single Nucleotide/genetics , Nigeria/epidemiology , Antimalarials/pharmacology , Antimalarials/therapeutic use , Alleles , Young Adult , Pregnancy Complications, Parasitic/parasitology , Pregnancy Complications, Parasitic/genetics , Pregnancy Complications, Parasitic/diagnosis , Drug Resistance, Multiple/genetics , Dihydropteroate Synthase/genetics , Tetrahydrofolate Dehydrogenase/genetics , Protozoan Proteins/genetics , Adolescent
15.
Biochem Pharmacol ; 225: 116243, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38697310

ABSTRACT

The spread of malarial parasites resistant to first-line treatments such as artemisinin combination therapies is a global health concern. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one) originally found in the cellular slime mould Dictyostelium discoideum. We previously showed that some derivatives of DIF-1, particularly DIF-1(+2) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) octan-1-one), exert potent antimalarial activities. In this study, we synthesised DIF-1(+3) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) nonan-1-one). We then evaluated the effects of DIF-1(+3) in vitro on Plasmodium falciparum and in vivo over 7 days (50-100 mg/kg/day) in a mouse model of Plasmodium berghei. DIF-1(+3) exhibited a half-maximal inhibitory concentration of approximately 20-30 % of DIF-1(+2) in three laboratory strains with a selectivity index > 263, including in strains resistant to chloroquine and artemisinin. Parasite growth and multiplication were almost completely suppressed by treatment with 100 mg/kg DIF-1(+3). The survival time of infected mice was significantly increased (P = 0.006) with no apparent adverse effects. In summary, addition of an acyl group to DIF-1(+2) to prepare DIF-1(+3) substantially enhanced antimalarial activity, even in drug-resistant malaria, indicating the potential of applying DIF-1(+3) for malaria treatment.


Subject(s)
Antimalarials , Hexanones , Plasmodium falciparum , Antimalarials/pharmacology , Animals , Mice , Hexanones/pharmacology , Hexanones/chemistry , Plasmodium falciparum/drug effects , Plasmodium berghei/drug effects , Malaria/drug therapy , Malaria/parasitology , Dictyostelium/drug effects , Acylation , Female , Hydrocarbons, Chlorinated
16.
Biochem Pharmacol ; 225: 116260, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38705539

ABSTRACT

Malaria is caused by an apicomplexan protozoan parasite, Plasmodium, and is transmitted through vectors. It remains a substantial health burden, especially in developing countries, leading to significant socioeconomic losses. Although the World Health Organization (WHO) has approved various antimalarial medications in the past two decades, the increasing resistance to these medications has worsened the situation. The development of drug resistance stems from genetic diversity among Plasmodium strains, impeding eradication efforts. Consequently, exploring innovative technologies and strategies for developing effective medications based on the host is crucial. Artemisinin and its derivatives (artemisinins) have been recommended by the WHO for treating malaria owing to their known effectiveness in killing the parasite. However, their potential to target the host for malaria treatment has not been investigated. This article concisely reviews the application of host-directed therapeutics, potential drug candidates targeting the host for treating malaria, and usage of artemisinins in numerous diseases. It underscores the importance of host-directed interventions for individuals susceptible to malaria, suggests the potential utility of artemisinins in host-directed malaria treatments, and posits that the modulation of host proteins with artemisinins may offer a means of intervening in host-parasite interactions. Further studies focusing on the host-targeting perspective of artemisinins can provide new insights into the mechanisms of artemisinin resistance and offer a unique opportunity for new antimalarial drug discovery.


Subject(s)
Antimalarials , Artemisinins , Malaria , Artemisinins/pharmacology , Artemisinins/therapeutic use , Humans , Antimalarials/pharmacology , Antimalarials/therapeutic use , Malaria/drug therapy , Animals , Drug Resistance/drug effects , Plasmodium/drug effects , Host-Parasite Interactions/drug effects
17.
Int J Antimicrob Agents ; 64(1): 107196, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38734217

ABSTRACT

With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1-2 h, the elimination half-life was 8-9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.


Subject(s)
Antimalarials , Healthy Volunteers , Malaria, Falciparum , Naphthyridines , Parasitemia , Plasmodium falciparum , Humans , Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Antimalarials/pharmacology , Antimalarials/administration & dosage , Naphthyridines/pharmacokinetics , Naphthyridines/therapeutic use , Naphthyridines/pharmacology , Naphthyridines/administration & dosage , Plasmodium falciparum/drug effects , Adult , Male , Young Adult , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Female , Parasitemia/drug therapy , Parasitemia/parasitology , Erythrocytes/drug effects , Erythrocytes/parasitology , Administration, Oral , Middle Aged , Treatment Outcome
18.
Acta Parasitol ; 69(2): 1244-1252, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38705947

ABSTRACT

PURPOSE: Artemisinin combination therapies, the first-line antimalarials in Nigeria, have reportedly suffered multiple failures in malaria treatment, hence the search for novel combination of other compounds. Methyl gallate and palmatine have been reported to exhibit antiplasmodial activities but the antimalarial activity of their combination has not been evaluated. Therefore, the evaluation of the combination of methyl gallate and palmatine for antimalarial activity in vitro and in vivo in the presence of piperine was carried out. MATERIALS AND METHODS: The inhibitory potential of methyl gallate and palmatine combination on ß-hematin (hemozoin) formation was studied in vitro. Also, the antimalarial activity of methyl gallate and palmatine combination with/without a bioenhancer (piperine) was evaluated in Plasmodium berghei NK65-infected mice. RESULTS: Methyl gallate and palmatine in the ratio 3:2 acted synergistically in vitro and had the highest inhibitory effect (IC50 = 0.73 µg/mL) on ß-hematin (hemozoin) formation. The 3:2 combination of methyl gallate and palmatine exhibited no antimalarial activity in vivo in the absence of piperine but caused reduction in parasitemia that exceeded 40% in the presence of piperine at the dose of 25 mg/kg body weight on days 6 and 8 post-inoculation in mice. CONCLUSION: The 3:2 combination of methyl gallate and palmatine in the presence of piperine exhibited antimalarial activity in vivo, possibly by synergistic inhibition of hemozoin formation which may cause accumulation of haem within the food vacuole of Plasmodium spp. and its death.


Subject(s)
Alkaloids , Antimalarials , Benzodioxoles , Berberine Alkaloids , Drug Synergism , Gallic Acid , Malaria , Piperidines , Plasmodium berghei , Polyunsaturated Alkamides , Animals , Polyunsaturated Alkamides/pharmacology , Antimalarials/pharmacology , Benzodioxoles/pharmacology , Piperidines/pharmacology , Malaria/drug therapy , Malaria/parasitology , Mice , Gallic Acid/pharmacology , Gallic Acid/analogs & derivatives , Alkaloids/pharmacology , Plasmodium berghei/drug effects , Berberine Alkaloids/pharmacology , Parasitemia/drug therapy , Inhibitory Concentration 50 , Hemeproteins
19.
ACS Infect Dis ; 10(6): 2276-2287, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38810215

ABSTRACT

Our previous work identified a series of 12 xanthoquinodin analogues and 2 emodin-dianthrones with broad-spectrum activities against Trichomonas vaginalis, Mycoplasma genitalium, Cryptosporidium parvum, and Plasmodium falciparum. Analyses conducted in this study revealed that the most active analogue, xanthoquinodin A1, also inhibits Toxoplasma gondii tachyzoites and the liver stage of Plasmodium berghei, with no cross-resistance to the known antimalarial targets PfACS, PfCARL, PfPI4K, or DHODH. In Plasmodium, inhibition occurs prior to multinucleation and induces parasite death following 12 h of compound exposure. This moderately fast activity has impeded resistance line generation, with xanthoquinodin A1 demonstrating an irresistible phenotype in both T. gondii and P. falciparum.


Subject(s)
Antimalarials , Drug Resistance , Plasmodium berghei , Plasmodium falciparum , Toxoplasma , Plasmodium falciparum/drug effects , Antimalarials/pharmacology , Antimalarials/chemistry , Toxoplasma/drug effects , Plasmodium berghei/drug effects , Animals , Anthraquinones/pharmacology , Anthraquinones/chemistry , Humans
20.
Phytochemistry ; 224: 114163, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38815883

ABSTRACT

Stereochemical investigations on the twigs and leaves of Solanum erianthum afforded five pairs of lignanamide enantiomers and a previously undescribed phenolic amide (3). Particularly, two pairs of previously undescribed lignanamide racemates (1a/1b-2a/2b) represent the first case of natural products that feature an unreported 5/5-fused N/O-biheterocyclic core. Their structures, including the absolute configurations, were determined unambiguously by using spectroscopic analyses and electronic circular dichroism calculations. A speculative biogenetic pathway for 1-3 was proposed. Interestingly, these lignanamides exhibited enantioselective antiplasmodial activities against drug-sensitive Plasmodium falciparum 3D7 strain and chloroquine-resistant Plasmodium falciparum Dd2 strain, pointing out that chirality plays an important role in drug development.


Subject(s)
Antimalarials , Plant Leaves , Plasmodium falciparum , Solanum , Plasmodium falciparum/drug effects , Antimalarials/chemistry , Antimalarials/pharmacology , Antimalarials/isolation & purification , Plant Leaves/chemistry , Solanum/chemistry , Stereoisomerism , Molecular Structure , Lignans/chemistry , Lignans/pharmacology , Lignans/isolation & purification , Amides/chemistry , Amides/pharmacology , Amides/isolation & purification , Structure-Activity Relationship , Parasitic Sensitivity Tests
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