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

Erik Koehne,Finn K. Hansen,Marcel Karl Walter Mackwitz,Matthew McCall,Ghyslain Mombo-Ngoma,Jana Held,Andrea Kreidenweiss,Rella Zoleko Manego

doi:10.1038/s41598-019-53912-w

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.

Highlights

Histone deacetylase (HDAC) enzymes are targets for the development of antimalarial drugs with a different mode of action to established antimalarials
Homologues of human HDAC6 (hHDAC6) proteins have been identified in P. falciparum and targeting class II HDACs might be a possibility to circumvent toxicity in humans[24]
The results of our investigation in clinical isolates resemble those previously obtained in laboratory strains[6,12], confirming that these compounds are active against a parasite population of high genetic diversity under selection pressure by the currently used antimalarial drugs[30,37]

Summary

Introduction

Histone deacetylase (HDAC) enzymes are targets for the development of antimalarial drugs with a different mode of action to established antimalarials. These compounds are classical HDAC inhibitors that have a cap-linker-zinc binding group structure with a peptoid-based cap group (N-alkyl glycine derivatives) Preclinical screens of these candidates identified potent activity against blood stages of P. falciparum laboratory strains 3D7 and Dd2 and against P. berghei liver stages with promising parasite selectivity indices[5,6]. These differences are mostly attributed to the partial immunity that is developed by the populations living in malaria endemic regions after multiple P. falciparum infections[34,35] It has not been investigated if the parasites themselves isolated from children or adults show different drug susceptibility profiles in in vitro assays. Age-dependent immune responses that cause a difference in the number of P. falciparum strains co-infecting a single individual, known as multiplicity of infection, could be one factor that provokes different susceptibility profiles in vitro

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Conclusion