title: 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.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48202, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Gupta
authors.forename: Ravikiran S
authors.initials: RS
authors.lastname: Yedidi
authors.forename: Sheeba
authors.initials: S
authors.lastname: Varghese
authors.forename: Ladislau C
authors.initials: LC
authors.lastname: Kovari
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woster
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001555:Benzene Derivatives; D004151:Dipeptides; D015800:Protozoan Proteins; D011725:Pyridines; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II; D002402:Cathepsin D