Mechanism-based inhibitors of the aspartyl protease plasmepsin II as potential antimalarial agents.

Abstract	Four aspartyl proteases known as plasmepsins are involved in the degradation of hemoglobin by Plasmodium falciparum, which causes a large percentage of malaria deaths. The enzyme plasmepsin II (Plm II) is the most extensively studied of these aspartyl proteases and catalyzes the initial step in the breakdown of hemoglobin by the parasite. Several groups have reported the design, synthesis, and evaluation of reversible peptidomimetic inhibitors of Plm II as potential antimalarial agents. We now report four peptidomimetic analogues, compounds 6-9, which are rationally designed to act as mechanism-based inhibitors of Plm II. Three of these analogues produce potent irreversible inactivation of the enzyme with IC(50) values in the low nanomolar range. Of these three compounds, two retain the low micromolar IC(50) values of the parent compound in Plasmodium falciparum (clone 3D7) infected erythrocytes. These analogues are the first examples of fully characterized mechanism-based inactivators for an aspartyl protease and show promise as novel antimalarial agents.
Authors	Deepak Gupta, Ravikiran S Yedidi, Sheeba Varghese, Ladislau C Kovari, Patrick M Woster
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 10 Pg. 4234-47 (May 27 2010) ISSN: 1520-4804 [Electronic] United States
PMID	20438064 (Publication Type: Journal Article)
Chemical References	Antimalarials Benzene Derivatives Dipeptides Protozoan Proteins Pyridines Aspartic Acid Endopeptidases plasmepsin II Cathepsin D
Topics	Animals Antimalarials (chemical synthesis, chemistry, pharmacology) Aspartic Acid Endopeptidases (antagonists & inhibitors) Benzene Derivatives (chemical synthesis, chemistry, pharmacology) CHO Cells Cathepsin D (antagonists & inhibitors) Cells, Cultured Cricetinae Cricetulus Dipeptides (chemical synthesis, chemistry, pharmacology) Erythrocytes (drug effects, parasitology) Humans Kinetics Models, Molecular Plasmodium falciparum (drug effects) Protozoan Proteins (antagonists & inhibitors) Pyridines (chemical synthesis, chemistry, pharmacology) Stereoisomerism Structure-Activity Relationship

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