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Annual Review of Microbiology Sep 2020Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. parasites resistant to... (Review)
Review
Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. parasites resistant to chloroquine, amodiaquine, or piperaquine harbor mutations in the chloroquine resistance transporter (PfCRT), a transporter resident on the digestive vacuole membrane that in its variant forms can transport these weak-base 4-aminoquinoline drugs out of this acidic organelle, thus preventing these drugs from binding heme and inhibiting its detoxification. The structure of PfCRT, solved by cryogenic electron microscopy, shows mutations surrounding an electronegative central drug-binding cavity where they presumably interact with drugs and natural substrates to control transport. susceptibility to heme-binding antimalarials is also modulated by overexpression or mutations in the digestive vacuole membrane-bound ABC transporter PfMDR1 ( multidrug resistance 1 transporter). Artemisinin resistance is primarily mediated by mutations in Kelch13 protein (K13), a protein involved in multiple intracellular processes including endocytosis of hemoglobin, which is required for parasite growth and artemisinin activation. Combating drug-resistant malaria urgently requires the development of new antimalarial drugs with novel modes of action.
Topics: Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Humans; Malaria, Falciparum; Membrane Transport Proteins; Mutation; Plasmodium falciparum; Protozoan Proteins; Quinolines
PubMed: 32905757
DOI: 10.1146/annurev-micro-020518-115546 -
The New England Journal of Medicine Sep 2023Although the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin...
BACKGROUND
Although the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in on the continent is troubling, given the lack of alternative treatments.
METHODS
In this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate-amodiaquine or artemether-lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in as predictive markers of partial resistance to artemisinin and screened for deletions in and that result in variable performance of histidine rich protein 2 (HRP2)-based rapid diagnostic tests for malaria.
RESULTS
We noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both and were identified in 16.9% of the parasites that carried the R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.
CONCLUSIONS
The emergence and spread of lineages with both -mediated partial resistance to artemisinin and deletions in and in Eritrea threaten to compromise regional malaria control and elimination campaigns. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry numbers, ACTRN12618001223224, ACTRN12618000353291, and ACTRN12619000859189.).
Topics: Humans; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Resistance; Eritrea; Malaria, Falciparum; Plasmodium falciparum; Prevalence
PubMed: 37754284
DOI: 10.1056/NEJMoa2210956 -
Nature Communications Jul 2023The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson's...
The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson's disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1's transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD.
Topics: Mice; Animals; Male; Parkinson Disease; Dopaminergic Neurons; Mesencephalon; Brain; Neuroprotective Agents; Disease Models, Animal; Nuclear Receptor Subfamily 4, Group A, Member 2
PubMed: 37463889
DOI: 10.1038/s41467-023-39970-9 -
Trends in Parasitology Aug 2022African children under 5 years of age bear the main burden of global malaria mortality. Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus... (Review)
Review
African children under 5 years of age bear the main burden of global malaria mortality. Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) given monthly during the rainy season is a highly effective malaria intervention for children aged between 3 months and 5 years living in the Sahel region, a region of intense but seasonal malaria transmission. This intervention is now being considered for other regions of Africa where malaria parasites are more drug resistant. Dihydroartemisinin-piperaquine (DP), an artemisinin-based combination therapy (ACT), has proved to be highly effective and well tolerated in intermittent preventive treatment in pregnant women and children. This combination may be a suitable alternative for SMC. Understanding the safety, pharmacokinetic and pharmacodynamic properties of antimalarial combination therapies is crucial in optimising dosing.
Topics: Amodiaquine; Antimalarials; Chemoprevention; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infant; Malaria; Pregnancy; Pyrimethamine; Seasons; Sulfadoxine
PubMed: 35688778
DOI: 10.1016/j.pt.2022.05.003 -
Heliyon Dec 2023Amodiaquine (AQ) was synthesized by a condensation reaction and characterized by experimental FT-IR, H and C nuclear magnetic resonance (NMR) and UV spectroscopies. In...
Amodiaquine (AQ) was synthesized by a condensation reaction and characterized by experimental FT-IR, H and C nuclear magnetic resonance (NMR) and UV spectroscopies. In the present work, Density Functional Theory (DFT) calculations. The structural and spectroscopic (FT-IR, H and C NMR and UV) data of amodiaquine molecule in ground state have been investigated by using Density Functional Theory (DFT). The calculations have been performed at the using B3LYP method with 6-311++G(d,p) and 6-311++G(2d, p) basis sets theory level were performed, first, to confirm its structure, then to explain its reactive nature through its molecular properties such as natural charges, local and global reactivity descriptors or natural bond orbital (NBO). Afterwards, the calculated properties were compared with experimental results. The H and C NMR chemical shifts were calculated by using the gauge-independent atomic orbital (GIAO) method, while the electronic UV-Vis spectrum is predicted using the time-dependent density functional theory (TD-DFT). Globally, the computerized results showed good agreement close similarity with the experimental values. The molecular properties such as natural charges, local and global reactivity descriptors, molecular electrostatic potential (MEP), natural bond orbital (NBO) of title molecule were calculated insights into the stability, reactivity and reactive sites on the molecule. The calculated energy band gap (E-E) value of AQ was found to be 4.09 eV suggesting that it could be considered as a hard molecule with high stability, supported by global reactivity descriptors. Molecular electrostatic potential (MEP) analysis revealed heteroatoms (oxygen and nitrogen) as the most putative nucleophilic sites when hydrogen atoms to which they are linked appear as electrophilic sites. The potential use of amodiaquine as non-linear optical (NLO) material and its thermodynamic indicators have also been assessed.
PubMed: 38076079
DOI: 10.1016/j.heliyon.2023.e22187 -
Briefings in Functional Genomics Sep 2019Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all... (Review)
Review
Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.
Topics: Aminoquinolines; Anti-Bacterial Agents; Antimalarials; Artemisinins; Atovaquone; Drug Resistance; Drug Resistance, Multiple; Folic Acid Antagonists; Humans; Malaria; Plasmodium falciparum; Plasmodium vivax; Quinine
PubMed: 31119263
DOI: 10.1093/bfgp/elz008 -
Nature Communications Jul 2023Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs)...
Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance. Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use. We show that introduction of TACTs could significantly delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs, and improving the chances of malaria elimination. We conclude that immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.
Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Folic Acid Antagonists
PubMed: 37516752
DOI: 10.1038/s41467-023-39914-3 -
International Journal of Molecular... Jun 2022Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation...
Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1-H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.
Topics: Drug Repositioning; Histamine; Histamine Agents; Humans; Multiple Sclerosis; Receptors, Histamine H4; Remyelination
PubMed: 35683024
DOI: 10.3390/ijms23116347