Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hitMore about Open Access at the Crick
Authors listK Jaudzems K Tars G Maurops N Ivdra M Otikovs J Leitans I Kanepe-Lapsa I Domraceva I Mutule P Trapencieris Michael Blackman A Jirgensons
Antimalarial hit 1SR (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 1SR bound to Plm 11 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.