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.
