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

Abstract

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. ■ SIGNIFICANCEFor the first time, we report some emerging antimalarial targets with special emphasis on mechanistic details of how they function. We believe such details are of value in medicinal chemistry toward facilitating rapid design of inhibitors. While considerable efforts have been made regarding drug target identification, the corresponding medicinal chemistry hit identification and hit-to-lead optimization have been insufficient. We believe this Perspective will contribute to bridging the gap between target discovery and inhibitor design.

Near-Term Quantum Classification Algorithms Applied to Antimalarial Drug Discovery

“…Recently, the resurgence of locally acquired malaria in U.S. regions of Florida and Texas has led to health advisories from the Centers for Disease Control (CDC) and increased drug resistance to current regimens , which suggests an urgent need to find novel antimalarials. , To date, malaria treatment has relied primarily on drugs that target the disease-causing Plasmodium falciparum asexual blood stages (ABS). These drugs include the 4-aminoquinolines piperaquine and amodiaquine, the antifolates pyrimethamine and sulfadoxine, as well as the endoperoxides artemisinin and its derivatives artesunate, artemether and dihydroartemisinin .…”

Peptidic Boronic Acid Plasmodium falciparum SUB1 Inhibitors with Improved Selectivity over Human Proteasome

“…Extensive efforts to control and eradicate malaria, particularly the availability of antimalarial drugs, have resulted in considerable reductions in mortality due to the disease over recent decades . However, widespread resistance of the parasite to many currently used drugs, including artemisinin-based combinations, is of great concern. − There is a widely accepted need to strengthen the antimalarial drug pipeline through the identification of new classes of antimalarial drugs with new modes of action. − …”