<p>Recent Progress in the Development of New Antimalarial Drugs with Novel Targets</p>

Abstract

Malaria is a major global health problem that causes significant mortality and morbidity annually. The therapeutic options are scarce and massively challenged by the emergence of resistant parasite strains, which causes a major obstacle to malaria control. To prevent a potential public health emergency, there is an urgent need for new antimalarial drugs, with single-dose cures, broad therapeutic potential, and novel mechanism of action. Antimalarial drug development can follow several approaches ranging from modifications of existing agents to the design of novel agents that act against novel targets. Modern advancement in the biology of the parasite and the availability of the different genomic techniques provide a wide range of novel targets in the development of new therapy. Several promising targets for drug intervention have been revealed in recent years. Therefore, this review focuses on the progress made on the latest scientific and technological advances in the discovery and development of novel antimalarial agents. Among the most interesting antimalarial target proteins currently studied are proteases, protein kinases, Plasmodium sugar transporter inhibitor, aquaporin-3 inhibitor, choline transport inhibitor, dihydroorotate dehydrogenase inhibitor, isoprenoid biosynthesis inhibitor, farnesyltransferase inhibitor and enzymes are involved in lipid metabolism and DNA replication. This review summarizes the novel molecular targets and their inhibitors for antimalarial drug development approaches.

Expansion Microscopy Reveals Plasmodium falciparum Blood-Stage Parasites Undergo Anaphase with A Chromatin Bridge in the Absence of Mini-Chromosome Maintenance Complex Binding Protein

“…One therapeutic strategy is the drug inhibition of DNA/RNA replication, and/or cell division, a method that is commonly used for the control of bacterial [7] and viral diseases [8], along with many types of cancer [9]. The distinctive division method of P. falciparum compared to its human host makes this an attractive strategy for P. falciparum drug design, yet no current antimalarials directly target DNA replication or cell division [10], highlighting the need for further investigation into this pathway.…”

Chemoproteomics for Plasmodium Parasite Drug Target Discovery

“…Many antimalarial agents have been proposed to target Plasmodium membrane proteins, such as cipargamin to PfATP4, [84] atovaquone to the cytochrome bc1 complex [85] and DSM265 to PfDHODH [86] . Various transporters have also been considered potential therapeutic targets [4,12] . Thus, the need remains to increase coverage of the membrane proteome to further enhance the utility of proteomics in target profiling.…”

“…Advances in cell‐based, high‐throughput phenotypic screens have significantly improved the efficiency of antimalarial drug discovery [3] . Thousands to millions of compounds have been evaluated for their activities against different Plasmodium life cycle stages, and dozens of them are currently in preclinical and clinical studies [4–8] . Although drugs can be approved without a full understanding of their mechanisms of action, a well‐characterized interaction between a candidate drug and its molecular target – possibly parasite or human biomolecules – can greatly facilitate the drug development process.…”

Expansion microsopy reveals Plasmodium falciparum blood-stage parasites undergo anaphase with a chromatin bridge in the absence of mini-chromosome maintenance complex binding protein

“…One therapeutic strategy is drug inhibition of DNA/RNA replication, and/or cell division, a method that is commonly used for control of bacterial [7] and viral diseases [8], along with many types of cancer [9]. The distinctive division method of P. falciparum compared to its human host makes this an attractive strategy for P. falciparum drug design, yet no current antimalarials directly target DNA replication or cell division [10]; highlighting the need for further investigation into this pathway.…”