Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Approximately 619,000 malaria deaths were reported in
2021, and
resistance to recommended drugs, including artemisinin-combination
therapies (ACTs), threatens malaria control. Treatment failure with
ACTs has been found to be as high as 93% in northeastern Thailand,
and parasite mutations responsible for artemisinin resistance have
already been reported in some African countries. Therefore, there
is an urgent need to identify alternative treatments with novel targets.
In this Perspective, we discuss some promising antimalarial drug targets,
including enzymes involved in proteolysis, DNA and RNA metabolism,
protein synthesis, and isoprenoid metabolism. Other targets discussed
are transporters, Plasmodium falciparum acetyl-coenzyme
A synthetase, N-myristoyltransferase, and the cyclic
guanosine monophosphate-dependent protein kinase G. We have outlined
mechanistic details, where these are understood, underpinning the
biological roles and hence druggability of such targets. We believe
that having a clear understanding of the underlying chemical interactions
is valuable to medicinal chemists in their quest to design appropriate
inhibitors.