Search for substrate-based inhibitors fitting the S2' space of malarial aspartic protease plasmepsin II.
Plasmepsin (Plm) has been identified as an important target for the development of new antimalarial drugs, since its inhibition leads to the starvation of Plasmodium falciparum. A series of substrate-based dipeptide-type Plm II inhibitors containing the hydroxymethylcarbonyl isostere as a transition-state mimic were synthesized. The general design principle was provision of a conformationally restrained hydroxyl group (corresponding to the set residue at the P2' position in native substrates) and a bulky unit to fit the S2' pocket.
Kiso
Aiko
A
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. kiso@mb.kyoto-phu.ac.jp
Hidaka
Koushi
K
Kimura
Tooru
T
Hayashi
Yoshio
Y
Nezami
Azin
A
Freire
Ernesto
E
Kiso
Yoshiaki
Y
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II