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Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults

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Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults. / Koehne, Erik; Kreidenweiss, Andrea; Zoleko Manego, Rella; McCall, Matthew; Mombo-Ngoma, Ghyslain; Mackwitz, Marcel Karl Walter; Hansen, Finn K; Held, Jana.

In: SCI REP-UK, Vol. 9, No. 1, 17336, 22.11.2019.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Koehne, E, Kreidenweiss, A, Zoleko Manego, R, McCall, M, Mombo-Ngoma, G, Mackwitz, MKW, Hansen, FK & Held, J 2019, 'Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults', SCI REP-UK, vol. 9, no. 1, 17336. https://doi.org/10.1038/s41598-019-53912-w

APA

Koehne, E., Kreidenweiss, A., Zoleko Manego, R., McCall, M., Mombo-Ngoma, G., Mackwitz, M. K. W., Hansen, F. K., & Held, J. (2019). Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults. SCI REP-UK, 9(1), [17336]. https://doi.org/10.1038/s41598-019-53912-w

Vancouver

Koehne E, Kreidenweiss A, Zoleko Manego R, McCall M, Mombo-Ngoma G, Mackwitz MKW et al. Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults. SCI REP-UK. 2019 Nov 22;9(1). 17336. https://doi.org/10.1038/s41598-019-53912-w

Bibtex

@article{a572f675c90b46fcb67f097319dc731e,
title = "Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults",
abstract = "Histone deacetylase (HDAC) enzymes are targets for the development of antimalarial drugs with a different mode of action to established antimalarials. Broad-spectrum HDAC-inhibitors show high potency against Plasmodium falciparum, but displayed some toxicity towards human cells. Inhibitors of human HDAC6 are new drug candidates with supposed reduced toxicity to human cells and favorable activities against laboratory P. falciparum strains. We investigated the potency of 12 peptoid-based HDAC-inhibitors against asexual stages of P. falciparum clinical isolates. Parasites representing different genetic backgrounds were isolated from adults and children with uncomplicated malaria in Gabon. Clinical studies on (non-HDAC-inhibitors) antimalarials, moreover, found lower drug efficacy in children, mainly attributed to acquired immunity with age in endemic areas. Therefore, we compared the in vitro sensitivity profiles of adult- and child-derived isolates to antimalarials (HDAC and standard drugs). All HDAC-inhibitors showed 50% inhibitory concentrations at nanomolar ranges with higher activities than the FDA approved reference HDAC-inhibitor SAHA. We propose peptoid-based HDAC6-inhibitors to be lead structures for further development as antimalarial chemotherapeutics. Our results further suggest no differences in activity of the tested antimalarials between P. falciparum parasites isolated from children and adults.",
keywords = "Adult, Child, Preschool, Drug Evaluation, Preclinical, Gabon, Genotype, Histone Deacetylase 6/antagonists & inhibitors, Histone Deacetylase Inhibitors/pharmacology, Humans, Inhibitory Concentration 50, Malaria, Falciparum/drug therapy, Middle Aged, Parasitic Sensitivity Tests, Peptoids/pharmacology, Plasmodium falciparum/drug effects, Young Adult",
author = "Erik Koehne and Andrea Kreidenweiss and {Zoleko Manego}, Rella and Matthew McCall and Ghyslain Mombo-Ngoma and Mackwitz, {Marcel Karl Walter} and Hansen, {Finn K} and Jana Held",
year = "2019",
month = nov,
day = "22",
doi = "10.1038/s41598-019-53912-w",
language = "English",
volume = "9",
journal = "SCI REP-UK",
issn = "2045-2322",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

RIS

TY - JOUR

T1 - Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults

AU - Koehne, Erik

AU - Kreidenweiss, Andrea

AU - Zoleko Manego, Rella

AU - McCall, Matthew

AU - Mombo-Ngoma, Ghyslain

AU - Mackwitz, Marcel Karl Walter

AU - Hansen, Finn K

AU - Held, Jana

PY - 2019/11/22

Y1 - 2019/11/22

N2 - Histone deacetylase (HDAC) enzymes are targets for the development of antimalarial drugs with a different mode of action to established antimalarials. Broad-spectrum HDAC-inhibitors show high potency against Plasmodium falciparum, but displayed some toxicity towards human cells. Inhibitors of human HDAC6 are new drug candidates with supposed reduced toxicity to human cells and favorable activities against laboratory P. falciparum strains. We investigated the potency of 12 peptoid-based HDAC-inhibitors against asexual stages of P. falciparum clinical isolates. Parasites representing different genetic backgrounds were isolated from adults and children with uncomplicated malaria in Gabon. Clinical studies on (non-HDAC-inhibitors) antimalarials, moreover, found lower drug efficacy in children, mainly attributed to acquired immunity with age in endemic areas. Therefore, we compared the in vitro sensitivity profiles of adult- and child-derived isolates to antimalarials (HDAC and standard drugs). All HDAC-inhibitors showed 50% inhibitory concentrations at nanomolar ranges with higher activities than the FDA approved reference HDAC-inhibitor SAHA. We propose peptoid-based HDAC6-inhibitors to be lead structures for further development as antimalarial chemotherapeutics. Our results further suggest no differences in activity of the tested antimalarials between P. falciparum parasites isolated from children and adults.

AB - Histone deacetylase (HDAC) enzymes are targets for the development of antimalarial drugs with a different mode of action to established antimalarials. Broad-spectrum HDAC-inhibitors show high potency against Plasmodium falciparum, but displayed some toxicity towards human cells. Inhibitors of human HDAC6 are new drug candidates with supposed reduced toxicity to human cells and favorable activities against laboratory P. falciparum strains. We investigated the potency of 12 peptoid-based HDAC-inhibitors against asexual stages of P. falciparum clinical isolates. Parasites representing different genetic backgrounds were isolated from adults and children with uncomplicated malaria in Gabon. Clinical studies on (non-HDAC-inhibitors) antimalarials, moreover, found lower drug efficacy in children, mainly attributed to acquired immunity with age in endemic areas. Therefore, we compared the in vitro sensitivity profiles of adult- and child-derived isolates to antimalarials (HDAC and standard drugs). All HDAC-inhibitors showed 50% inhibitory concentrations at nanomolar ranges with higher activities than the FDA approved reference HDAC-inhibitor SAHA. We propose peptoid-based HDAC6-inhibitors to be lead structures for further development as antimalarial chemotherapeutics. Our results further suggest no differences in activity of the tested antimalarials between P. falciparum parasites isolated from children and adults.

KW - Adult

KW - Child, Preschool

KW - Drug Evaluation, Preclinical

KW - Gabon

KW - Genotype

KW - Histone Deacetylase 6/antagonists & inhibitors

KW - Histone Deacetylase Inhibitors/pharmacology

KW - Humans

KW - Inhibitory Concentration 50

KW - Malaria, Falciparum/drug therapy

KW - Middle Aged

KW - Parasitic Sensitivity Tests

KW - Peptoids/pharmacology

KW - Plasmodium falciparum/drug effects

KW - Young Adult

U2 - 10.1038/s41598-019-53912-w

DO - 10.1038/s41598-019-53912-w

M3 - SCORING: Journal article

C2 - 31758015

VL - 9

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

M1 - 17336

ER -