title: Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit.
abstract: Antimalarial hit 1 SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1 SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Kristaps
authors.initials: K
authors.lastname: Jaudzems
authors.affiliation: Biomedical Research and Study Centre , Ratsupites 1, Riga LV-1067, Latvia.
authors.forename: Kaspars
authors.initials: K
authors.lastname: Tars
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Gundars
authors.initials: G
authors.lastname: Maurops
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Natalija
authors.initials: N
authors.lastname: Ivdra
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Martins
authors.initials: M
authors.lastname: Otikovs
authors.affiliation: Biomedical Research and Study Centre , Ratsupites 1, Riga LV-1067, Latvia.
authors.forename: Janis
authors.initials: J
authors.lastname: Leitans
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Iveta
authors.initials: I
authors.lastname: Kanepe-Lapsa
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Ilona
authors.initials: I
authors.lastname: Domraceva
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Ilze
authors.initials: I
authors.lastname: Mutule
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Peteris
authors.initials: P
authors.lastname: Trapencieris
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research , The Ridgeway, Mill, Hill, London NW7 1AA, U.K.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Aigars
authors.initials: A
authors.lastname: Jirgensons
keywords: Cathepsin D; Malaria; Plasmodium falciparum; hydroxyethylamine; inhibition; plasmepsins; structure-guided optimization