Structure-Guided Optimization of Novel Inhibitors of Plasmodium Lysyl-tRNA Synthetase with Multistage Activity against Malaria Parasites

Donna Huber on June 2, 2026

Diagram showing the chemical optimization of a compound with multistage antimalarial activity for malaria treatment and a 3D structure (yellow) bound to Plasmodium Lysyl-tRNA Synthetase, highlighting key amino acid interactions.

A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγnull (SCID) mouse model. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor (30) with an extended half-life to reduce the dose regimen to a single-dose cure. Compound 30 displayed a long half-life across preclinical species, favorable safety, and activity across Plasmodium species as well as against drug-resistant and sensitive P. falciparum strains and field isolates. Unfortunately, 30 lacked oral bioavailability, which could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future KRS programs in delivering a clinical candidate with this novel mode of action.

Barbara Forte, Fiona Bellany, Peter S Campbell, Giulia Chemi, Alice Dawson, Mark Anderson, Yaw Aniweh, Anna Y Burkhard, Anna Caroline Campos Aguiar, Alisje Churchyard, Caitlin A Cooper, Amália Dos Santos Ferreira, Mufuliat Toyin Famodimu, Francis G Fang, Xiao Hu, Tonnie Huijs, Delphine Baud, Chimed Jansen, María Belén Jiménez Díaz, Roger Bonnert, Susan Boyd, Benigno Crespo-Fernández, Branko Mitasev, Simone Montagna, Sachel Mok, Dinakaran Murugesan, Sunil K Narwal, Neil R Norcross, John Okombo, Heekuk Park, Caroline Peet, Dhelio B Pereira, John M Post, Janette Reader, Jennifer Riley, David A Robinson, Raku Shinkyo, Frederick R C Simeons, Laura Simpson, Alasdair Smith, Dennis Smith, Josefine Striepen, Carolina B G Teles, Rianne van der Laak, Anne-Catrin Uhlemann, Amélie Vantaux, Caroline Wilson, Benoît Witkowski, Gavin Wood, Tomas Yeo, Fabio Zuccotto, Iñigo Angulo-Barturen, Jake Baum, Judith M Bolscher, Rafael Victorio Carvalho Guido, Lyn-Marié Birkholtz, Michael J Delves, Laurent Dembele, David A Fidock, Francisco Javier Gamo, Dennis E Kyle, Steven P Maher, Jean Popovici, Chris Walpole, Fabian Gusovsky, Paul A Willis, Kevin D Read, Ian H Gilbert, Beatriz Baragaña. J Med Chem. 2026 Jun 2. doi: 10.1021/acs.jmedchem.6c00823.