4-Aminoquinolines—Past, present, and future; A chemical perspective

O’Neill, Paul M.; Bray, Patrick G.; Hawley, S R; Ward, Stephen A.; Park, B K

doi:10.1016/s0163-7258(97)00084-3

Cited by 255 publications

(169 citation statements)

References 103 publications

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“…All of these compounds are believed to act, at least in part, by complexing with heme products (35,36). Possibly, PfCRT mutations affect accumulation by altering drug flux across the digestive vacuole membrane.…”

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confidence: 99%

Chloroquine Resistance in Plasmodium falciparum Malaria Parasites Conferred by pfcrt Mutations

Sidhu

Verdier-Pinard

Fidock

2002

Science

644

663

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Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance. Here, we provide conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials warrant further investigation as agents to control chloroquine-resistant falciparum malaria.Chloroquine has for decades been the primary chemotherapeutic means of malaria treatment and control (1). This safe and inexpensive 4-aminoquinoline compound accumulates inside the digestive vacuole of the infected red blood cell, where it is believed to form complexes with toxic heme moieties and interfere with detoxification mechanisms that include heme sequestration into an inert pigment called hemozoin (2-4). Chloroquine resistance (CQR) was first reported in Southeast Asia and South America and has now spread to the vast majority of malaria-endemic countries (1). pfcrt was recently identified as a candidate gene for CQR after the analysis of a genetic cross between a chloroquine-resistant clone (Dd2, Indochina) and a chloroquine-sensitive clone (HB3, Honduras) (5-7). The PfCRT protein localizes to the digestive vacuole membrane and contains 10 putative transmembrane domains (7,8). Point mutations in PfCRT, including the Lys 76 → Thr (K76T) mutation in the first predicted transmembrane domain, show an association with CQR in field isolates and clinical studies (7,9,10). Episomal complementation assays demonstrated a low-level, atypical CQR phenotype in chloroquine-selected, transformed, pseudo-diploid parasite lines that coexpressed the Dd2 form of pfcrt (containing eight point mutations; Table 1), under the control of a heterologous promoter, with the wild-type endogenous allele (7).To address whether mutations in pfcrt are sufficient to confer CQR, we implemented an allelic exchange approach to replace the endogenous pfcrt allele of a chloroquine-sensitive line (GC03) with pfcrt alleles from chloroquine-resistant lines of Asian, African, or South American origin (Table 1) (fig. S1) (11). This approach maintained the endogenous promoter and terminator regulatory elements for correct stage-specific expression and did not use chloroquine during the selection procedure. As a result of this gene's highly interrupted nature * To whom correspondence should be addressed. dfidock@aecom.yu.edu. Wootton et al. (39) recently presented compelling evidence for rapid evolutionary sweeps of mutant pfcrt sequences throughout malaria-endemic areas, starting from a limited number of initi...

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confidence: 99%

Chloroquine Resistance in Plasmodium falciparum Malaria Parasites Conferred by pfcrt Mutations

Sidhu

Verdier-Pinard

Fidock

2002

Science

644

663

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“…4,5 CQ is an antimalarial agent, also used for treatment of chronic inflammatory and autoimmune diseases. 27 Mechanisms of antiinflammatory effects of CQ are not completely clear; most probably CQ interferes with presentation and recognition of antigens by blocking of lysosomal processing of major histocompatibility complex molecules. 27 An ability of CQ to inhibit proton pumps, and therefore disrupt proton gradients leading to lysosome pH decrease, has been amply documented.…”

Section: Discussionmentioning

confidence: 99%

“…27 Mechanisms of antiinflammatory effects of CQ are not completely clear; most probably CQ interferes with presentation and recognition of antigens by blocking of lysosomal processing of major histocompatibility complex molecules. 27 An ability of CQ to inhibit proton pumps, and therefore disrupt proton gradients leading to lysosome pH decrease, has been amply documented. 27,28 Acidification of lysosomes is a key event in the pathogenesis of anthrax, being essential for dissociation of internalized PA-LF complexes.…”

Section: Discussionmentioning

confidence: 99%

“…27 An ability of CQ to inhibit proton pumps, and therefore disrupt proton gradients leading to lysosome pH decrease, has been amply documented. 27,28 Acidification of lysosomes is a key event in the pathogenesis of anthrax, being essential for dissociation of internalized PA-LF complexes. Hence, agents interfering with this process may have practical applications.…”

Section: Discussionmentioning

confidence: 99%

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Ultrastructural features of lymphocyte suppression induced by anthrax lethal toxin and treated with chloroquine

Hirsh

Manov

Cohen-Kaplan³

et al. 2007

Laboratory Investigation

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Antibacterial therapy does not fully protect against anthrax because of severe systemic intoxication. Lysosomal processing of anthrax lethal toxin (LTX) is a key event in the disease pathogenesis, and agents interfering with this process, like chloroquine (CQ), may have practical applications. Although LTX is known to induce T-cell suppression, precise mechanisms of this phenomenon are not completely characterized. In the present study, we investigated alterations of lymphocyte ultrastructure caused by LTX and associated with favorable effect of CQ on the LTX-related dysfunction. Peripheral blood lymphocytes were activated via CD3 crosslinking in the presence or absence of LTX and CQ, and examined by transmission electron microscopy, flow cytometry and immunoblotting. Crosslinking of CD3 induced ultrastructural signs of lymphocyte activation, mostly disappeared after LTX treatment. The cell ultrastructure was well preserved in LTX-treated cells, despite dose-and time-dependent inhibition of T-cell function associated with impaired activation of mitogen-activated protein kinase. Regardless of intracellular signaling abnormalities, LTX did not decrease T-cell viability. CQ restored expression of CD69 (Po0.001) and improved phosphorylation of p38 (P ¼ 0.022) in LTXexposed T lymphocytes. The exposure of cells to CQ, with or without LTX, led to appearance of many phagolysosomes with heterogeneous content, possibly representing unprocessed internalized material. In conclusion, LTX suppressed Tcell functions, but did not affect the viability and caused no ultrastructural damage. Ultrastructural observations indicated that CQ reduced harmful effects of LTX, possibly by interfering with lysosomal activity.

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“…Quinoline antimalarials and related aryl alcohols are based on the chemical structure of quinine, an active ingredient of Cinchona bark, which was first imported into Europe from Peru for antimalarial use in the XVII century by the Jesuits. The dependence on raw material for its extraction and the opportunities presented by its structural elucidation led to the development of fully synthetic and inexpensive 4-aminoquinoline antimalarials -notably chloroquine and amodiaquine (O'Neill et al 1998). Artemisinin is the active ingredient of the Chinese herb "qinghao" (Artemisia annua) that was traditionally used for treating fevers.…”

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confidence: 99%

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

Basso

Silva

Fett-Neto

et al. 2005

Mem. Inst. Oswaldo Cruz

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4-Aminoquinolines—Past, present, and future; A chemical perspective

Cited by 255 publications

References 103 publications

Chloroquine Resistance in Plasmodium falciparum Malaria Parasites Conferred by pfcrt Mutations

Chloroquine Resistance in Plasmodium falciparum Malaria Parasites Conferred by pfcrt Mutations

Ultrastructural features of lymphocyte suppression induced by anthrax lethal toxin and treated with chloroquine

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

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