Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit
ACS Medicinal Chemistry Letters 2014
Kristaps Jaudzems, Kaspars Tārs, Gundars Maurops, Natalija Ivdra, Martins Otikovs, Janis Leitans, Iveta Kanepe-Lapsa, Ilona Domraceva, Ilze Mutule, Peteris Trapencieris, Michael J. Blackman, Aigars 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 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.


Atslēgas vārdi
Malaria; Plasmodium falciparum; plasmepsins; Cathepsin D; inhibition; structure-guided optimization; hydroxyethylamine
DOI
10.1021/ml4004952
Hipersaite
http://pubs.acs.org/doi/abs/10.1021/ml4004952

Jaudzems, K., Tars, K., Maurops, G., Ivdra, N., Otikovs, M., Leitans, J., Kanepe-Lapsa, I., Domraceva, I., Mutule, I., Trapencieris, P., Blackman, M., Jirgensons, A. Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit. ACS Medicinal Chemistry Letters, 2014, Vol.5, No.4, 373.-377.lpp. ISSN 1948-5875. Pieejams: doi:10.1021/ml4004952

Publikācijas valoda
English (en)
RTU Zinātniskā bibliotēka.
E-pasts: uzzinas@rtu.lv; Tālr: +371 28399196