Proteases of Plasmodium falciparum as Potential Drug Targets and Inhibitors Thereof

Abstract

Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious diseases worldwide killing more than 1 million people per year. The emergence of multidrug-resistant parasites highly demands a steadfast and continuous search not only for new targets but also for new anti-infectives addressing the known ones. As proteases in general have been proven to be excellent drug targets and the development of inhibitors has frequently resulted in approved drugs, this review will only focus on the proteases of Plasmodium falciparum as drug targets. The completion of the sequencing of the Plasmodium falciparum genome in 2002 lead to the discovery of nearly 100 putative proteases encoded therein. Within this review, only those proteases and inhibitors thereof will be discussed in more detail, in which their biological function has been determined undoubtedly or in those cases, in which the development of specific inhibitors has significantly contributed to the understanding of the underlying biological role of the respective protease thus validating the role as promising drug target.

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

“…These recent advances have allowed development of bioassays based upon validated targets for drug screening, or targets still in the process of validation (for review see , Prabhu & Patravale, 2011, Sahu et al, 2008) : haem polymerization (O'Neill et al, 2006), pyrimidine, purine, folate (Hyde, 2007), lipid (Wengelnik et al, 2002), shikimate (McRobert et al, 2005), non-mevalonate (Wiesner & Jomaa, 2007) and other apicoplast metabolisms (Sato & Wilson, 2005), mitochondrial electron transport (Mather et al, 2007), redox homeostasis (Bauer et al, 2006), protein prenylation (Van Voorhis et al, 2007), proteases (Wegscheid-Gerlach et al, 2010), kinases (Doerig & Meijer, 2007)... Some of them are detailed below.…”

“…Although none of the currently marketed antimalarials is targeting plasmodial proteases, this class of enzymes, which is involved in a wide diversity of biological pathways during the parasite life cycle, has been the subject of intense investigations for the last decades www.intechopen.com (Wegscheid-Gerlach et al, 2010). The cystein and aspartyl endoproteases involved in the essential pathway of haemoglobin degradation now known as falcipain-2, 2' and -3 and plasmepsin-I, -II, -III (or HAP, for histo-aspartyl protease) and -IV have first emerged as promising protease targets.…”

Antimalarial Peptides: The Long and the Short of It

“…These have been extensively reviewed [14][15][16] and (along with peptidic inhibitors of other protein-modifying enzymes such as histone deacetylases) will not be covered here due to space limitations. It is however worth mentioning an interesting approach to delivery of a peptidase inhibitor taken by Dhawan et al [17], who used the Antennapedia homeoprotein internalization domain to enhance penetration of an ankyrin peptide into blood-stage P. falciparum.…”

The Substrate Binding Preferences of Plasmodium Thymidylate Kinase

“…2,3) Lack of an effective vaccination and the spread of drug resistance necessitate the development of new drug targets. In the development of antimalarial drugs, it may be suitable to select targets from pathways present in the parasite but absent in humans.…”