Widespread release of translational repression across Plasmodium's host-to-vector transmission event.

Malaria parasites must respond quickly to environmental changes, including during their transmission between mammalian and mosquito hosts. Therefore, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. While the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not.

Metabolite profiling of Artemisia afra and Artemisia annua extracts reveals divergent effects on Plasmodium falciparum.

Background: Artemisia spp. have been used for millennia in traditional medicine to treat a variety of ailments, including malaria. Extracts of Artemisia afra and A.

Gametocyte production and transmission fitness of African and Asian isolates with differential susceptibility to artemisinins.

The emergence of parasites partially resistant to artemisinins (ART-R) poses a significant threat to recent gains in malaria control. ART-R has been associated with PfKelch13 (K13) mutations, which differ in fitness costs. This study investigates the gametocyte production and transmission fitness of African and Asian isolates with different K13 genotypes across multiple mosquito species.

TKK130 is a 3-Hydroxy-Propanamidine (HPA) with Potent Antimalarial Activity and a High Barrier to Resistance.

Malaria continues to pose a significant burden on populations in endemic areas and requires innovative treatment options. Here, we report the synthesis and preclinical evaluation of the novel 3-hydroxypropanamidine (HPA) , which shows excellent antiplasmodial activity against drug-sensitive and -resistant strains. Moreover, in various human cell lines, the compound shows no cytotoxicity and excellent parasite selectivity.

Safety, tolerability, pharmacokinetics, and antimalarial activity of MMV533: a phase 1a first-in-human, randomised, ascending dose and food effect study, and a phase 1b Plasmodium falciparum volunteer infection study.

Background: Novel antimalarials are needed to address emerging resistance to artemisinin and partner drugs. We did two trials to evaluate safety, tolerability, pharmacokinetics, and activity against blood stage Plasmodium falciparum for the drug candidate MMV533.

Methods: A phase 1a first-in-human (FIH) trial was conducted at Nucleus Network (Melbourne, VIC, Australia).

Plasmodium falciparum African PfCRT Mutant Isoforms Conducive to Piperaquine Resistance are Infrequent and Impart a Major Fitness Cost.

Background: Piperaquine, used in combination with dihydroartemisinin, has been identified as a promising partner drug for uncomplicated treatment and chemoprevention of Plasmodium falciparum malaria in Africa. In light of the earlier spread of piperaquine resistance in Southeast Asia, mediated primarily by mutations in the drug efflux transporter PfCRT, we have explored whether PfCRT mutations would represent a probable path to piperaquine resistance becoming established in Africa.

Methods: We edited PfCRT mutations known to mediate piperaquine resistance in Southeast Asia into P.

A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity.

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants.

Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs.

Targeting CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment.

Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by increasing this number each year. New medicines with novel mechanisms of action are, therefore, urgently needed. In this work, we solved the cocrystal structure of the essential malarial kinase CLK3 with the reversible inhibitor TCMDC-135051 (), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome.

Unraveling the complexities of ApiAP2 regulation in Plasmodium falciparum.

The regulation of gene expression in Plasmodium spp., the causative agents of malaria, relies on precise transcriptional control. Malaria parasites encode a limited repertoire of sequence-specific transcriptional regulators dominated by the apicomplexan APETALA 2 (ApiAP2) protein family.

A MORC protein complex modulates epigenetic control of gene expression through interaction with heterochromatin.

Dynamic control of gene expression is critical for blood stage development of malaria parasites. Here, we used multi-omic analyses to investigate transcriptional regulation by the chromatin-associated microrchidia protein, MORC, during asexual blood stage development of the human malaria parasite . We show that MORC (PF3D7_1468100) interacts with a suite of nuclear proteins, including APETALA2 (ApiAP2) transcription factors (AP2-G5, AP2-O5, AP2-I, PF3D7_0420300, PF3D7_0613800, PF3D7_1107800, and PF3D7_1239200), a DNA helicase DS60 (PF3D7_1227100), and other chromatin remodelers (CHD1 and EELM2).

Identification of the drug/metabolite transporter 1 as a marker of quinine resistance in a NF54×Cam3.II genetic cross.

The genetic basis of resistance to quinine (QN), a drug used to treat severe malaria, has long been enigmatic. To gain further insight, we used FRG-NOD human liver-chimeric mice to conduct a genetic cross between QN-sensitive and QN-resistant parasites, which also differ in their susceptibility to chloroquine (CQ). By applying different selective conditions to progeny pools prior to cloning, we recovered 120 unique recombinant progeny.

Towards next-generation treatment options to combat Plasmodium falciparum malaria.

Malaria, which is caused by infection of red blood cells with Plasmodium parasites, can be fatal in non-immune individuals if left untreated. The recent approval of the pre-erythrocytic vaccines RTS, S/AS01 and R21/Matrix-M has ushered in hope of substantial reductions in mortality rates, especially when combined with other existing interventions. However, the efficacy of these vaccines is partial, and chemotherapy remains central to malaria treatment and control.

Contrasting genomic epidemiology between sympatric Plasmodium falciparum and Plasmodium vivax populations.

The malaria parasites Plasmodium falciparum and Plasmodium vivax differ in key biological processes and associated clinical effects, but consequences on population-level transmission dynamics are difficult to predict. This co-endemic malaria study from Guyana details important epidemiological contrasts between the species by coupling population genomics (1396 spatiotemporally matched parasite genomes, primarily from 2020-21) with sociodemographic analysis (nationwide patient census from 2019). We describe how P.

Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets.

Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance.

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5).

The bio-larvicide var. is effective against , either dissolved in water or delivered through eco-compatible chitosan-based hydrogels.

Mosquito control, which is not always easily accomplished, is further complicated by the spread of invasive species. This is the case of , a mosquito native to East Asia, whose presence has been recorded in several European countries, including Italy. This mosquito found suitable ecological conditions in central Europe in general, and in northern Italy in particular, as shown by the ongoing expansion of its distribution.

Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3.

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold.