2. Academic Validation
  3. Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit

Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit

  • ACS Med Chem Lett. 2014 Jan 13;5(4):373-7. doi: 10.1021/ml4004952.
Kristaps Jaudzems 1,  Kaspars Tars 2,  Gundars Maurops 1,  Natalija Ivdra 1,  Martins Otikovs 1,  Janis Leitans 2,  Iveta Kanepe-Lapsa 1,  Ilona Domraceva 1,  Ilze Mutule 1,  Peteris Trapencieris 1,  Michael J Blackman 3,  Aigars Jirgensons 1
Affiliations

Affiliations

  • 1 Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
  • 2 Biomedical Research and Study Centre , Ratsupites 1, Riga LV-1067, Latvia.
  • 3 Division of Parasitology, MRC National Institute for Medical Research , The Ridgeway, Mill, Hill, London NW7 1AA, U.K.
PMID: 24900843 DOI: 10.1021/ml4004952
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.

Keywords

Cathepsin D; Malaria; Plasmodium falciparum; hydroxyethylamine; inhibition; plasmepsins; structure-guided optimization.

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