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, Jahrgang 9, Nr. 1, 17336, 22.11.2019.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -