Inhibition of lysine-specific demethylase 1 as an antimalarial target by polyamine analogues

Abstract

According to the World Health Organization, malaria has been classified as one of the three most important infectious diseases in Africa. The number of malaria cases is still on the increase in various countries, such as Rwanda and Zambia, which highlights the fragility of malaria control and the need to maintain and improve control programs. An innovative strategy for developing new antimalarial agents is through targeting epigenetic regulatory mechanisms in the malarial parasite, Plasmodium falciparum. Histone posttranslational modifications (PTMs) are factors contributing to epigenetic regulation in P. falciparum parasites. The epigenetic regulatory enzyme, Lysine-specific demethylase 1 (LSD1), has the ability to remove methyl groups from mono- and dimethylated lysine residues and is a regulator of gene expression through the modulation of chromatin structure. Polyamine analogues have been described as epi-drugs that target cell cycle development by blocking epigenetic control mechanisms in mammalian cells. A library of polyamine analogues were tested in cancer cells and found to specifically inhibit LSD1. In addition, these analogues were shown to have antiplasmodial activity against a drug-sensitive parasite strain, with IC50 values ranging from 88-100 nM but were metabolically unstable in vivo. In an attempt to overcome this in vivo hurdle, the leading compound was fluorinated at four different positions and tested for improved antiplasmodial activity and selectivity towards the parasites. Furthermore, the effect of the compounds on epigenetic regulatory mechanisms, through inhibition of LSD1 activity, was investigated. The analogues showed inhibition of parasite proliferation at low nanomolar concentrations and were very selective towards the parasites with low resistance indices. The leading compound showed reversible cytotoxicity towards parasite proliferation in addition to inhibitory activity against LSD1 and therefore, epigenetic regulatory changes. The approach taken in this dissertation is novel as none of the currently available antimalarials target LSD1 and as such, adds valuable information to future perspectives for drug design.