Mode of action of quinoline antimalarial drugs in red blood cells infected by
            <i>Plasmodium falciparum</i>
            revealed in vivo

Kapishnikov, Sergey; Staalsøe, Trine; Yang, Yang; Lee, Jiwoong; Pérez-Berná, Ana J.; Pereiro, Eva; Werner, Stephan; Guttmann, Peter; Leiserowitz, Leslie; Als‐Nielsen, J.

doi:10.1073/pnas.1910123116

Cited by 78 publications

(89 citation statements)

References 40 publications

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“…Considering CQ/HCQ and pathogens direct interactions, only the interference of CQ and Plasmodium, via hemozoin crystallization inhibition leading to parasite death, has been clearly documented (58). Immunity against infectious agents, including bacteria, virus or fungus, also involve vessels, and inflammation at the endothelium level (59).…”

Section: Other Effects Of Cq/hcqmentioning

confidence: 99%

Beyond Anti-viral Effects of Chloroquine/Hydroxychloroquine

et al. 2020

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Section: Other Effects Of Cq/hcqmentioning

confidence: 99%

Beyond Anti-viral Effects of Chloroquine/Hydroxychloroquine

et al. 2020

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“…Model M1a allows two classes of sites under neutral evolution (ω = 1) and purifying selection (0 ≤ ω < 1), whereas model M2a adds a third class of sites to model M1a as positive selection (ω > 1). In the discrete model M3, several classes (k = [3][4][5] in this study) of independent ω were estimated, each of them being associated with a specific proportion. Model M7 assumes a β-distribution of ten ω ratios limited to the interval [0, 1] with two shape parameters p and q.…”

Section: Analysis Of Selective Pressures Acting On Crtmentioning

confidence: 99%

Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter

Coppée

Sabbagh

Clain

2020

Sci Rep

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Mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcRt) confer resistance to several antimalarial drugs such as chloroquine (cQ) or piperaquine (ppQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite transporter (DMt) superfamily, the vacuolar transporter pfcRt may translocate substrate molecule(s) across the membrane of the digestive vacuole (DV), a lysosome-like organelle. However, the physiological substrate(s), the transport mechanism and the functional regions of pfcRt remain to be fully characterized. Here, we hypothesized that identification of evolutionary conserved sites in a tertiary structural context could help locate putative functional regions of PfCRT. Hence, site-specific substitution rates were estimated over Plasmodium evolution at each amino acid sites, and the pfcRt tertiary structure was predicted in both inward-facing (open-to-vacuole) and occluded states through homology modeling using DMt template structures sharing <15% sequence identity with PfCRT. We found that the vacuolar-half and membrane-spanning domain (and especially the transmembrane helix 9) of PfCRT were more conserved, supporting that its physiological substrate is expelled out of the parasite DV. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain. Through structural comparison with experimentallycharacterized DMT transporters, we identified several conserved PfCRT amino acid sites located in this pocket as robust candidates for mediating substrate transport. finally, in silico mutagenesis revealed that drug resistance mutations caused drastic changes in the electrostatic potential of the transporter vacuolar entry and pocket, facilitating the escape of protonated cQ and ppQ from the parasite DV.

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“…Other experimentally identified CQ/HCQ targets include phospholipase A2 ( 56 – 59 ), porphyrins ( 60 , 61 ), and even DNA at high CQ concentrations around 1 mM ( 42 ) ( Table 2 ).…”

Section: General Mechanisms Of Cq/hcq Actionsmentioning

confidence: 99%

Immune Modulation as a Therapeutic Option During the SARS-CoV-2 Outbreak: The Case for Antimalarial Aminoquinolines

et al. 2020

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The rapid spread, severity, and lack of specific treatment for COVID-19 resulted in hasty drug repurposing. Conceptually, trials of antivirals were well-accepted, but twentieth century antimalarials sparked an impassioned global debate. Notwithstanding, antiviral and immunomodulatory effects of aminoquinolines have been investigated in vitro, in vivo and in clinical trials for more than 30 years. We review the mechanisms of action of (hydroxy)chloroquine on immune cells and networks and discuss promises and pitfalls in the fight against SARS-CoV-2, the agent of the COVID-19 outbreak.

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Mode of action of quinoline antimalarial drugs in red blood cells infected by Plasmodium falciparum revealed in vivo

Cited by 78 publications

References 40 publications

Beyond Anti-viral Effects of Chloroquine/Hydroxychloroquine

Beyond Anti-viral Effects of Chloroquine/Hydroxychloroquine

Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter

Immune Modulation as a Therapeutic Option During the SARS-CoV-2 Outbreak: The Case for Antimalarial Aminoquinolines

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