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Publikācija: Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit

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Publikācijas valoda English (en)
Nosaukums oriģinālvalodā Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit
Pētniecības nozare 1. Dabaszinātnes
Pētniecības apakšnozare 1.4. Ķīmija
Autori 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
Atslēgas vārdi Malaria; Plasmodium falciparum; plasmepsins; Cathepsin D; inhibition; structure-guided optimization; hydroxyethylamine
Anotācija 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.
DOI: 10.1021/ml4004952
Hipersaite: http://pubs.acs.org/doi/abs/10.1021/ml4004952 
Atsauce 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
Papildinformācija Citējamību skaits:
ID 19095