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Publications

Journal Article Ahead of print

PubMed: 42227818 DOI: 10.1021/acs.jmedchem.6c00823

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

J Med Chem

Authors: 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 … and 19 other authors

Affiliations

  • Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), College of Basic and Applied Sciences, University of Ghana, Accra LG54, Ghana.
  • Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • Department of Microbiology, Immunology, and Parasitology, Federal University of São Paulo, São Paulo, São Paulo CEP 04023-062, Brazil.
  • Department of Life Sciences, Imperial College, London SW7 2AZ, U.K.
  • Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602-0002, United States.
  • Oswaldo Cruz Foundation, Leishmaniasis and Malaria Bioassay Platform, Porto Velho, Rondônia CEP 76812-245, Brazil.
  • Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
  • Eisai, Inc. 35 Cambridge Park Drive Suite 200, Cambridge, Massachusetts 02140, United States.
  • TropIQ Health Sciences, Nijmegen 6534 AT, The Netherlands.
  • MMV Medicines for Malaria Venture, ICC, Geneva 1215, Switzerland.
  • The Art of Discovery, Derio 48160, Spain.
  • Global Health Medicines R&D, GSK, Tres Cantos, Madrid 28760, Spain.
  • Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • Research Center in Tropical Medicine of Rondônia, Porto Velho, Rondônia CEP 76812-329, Brazil.
  • Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control University of Pretoria, Hatfield, Pretoria 0028, South Africa.
  • Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh 120210, Cambodia.
  • São Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo CEP 13563-120, Brazil.

Abstract

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-IL2Rγ null (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.

MeSH

Ligases, Malaria, Pharmaceutical Preparations, Amino Acyl-Trna Synthetases, Parasites, Rna, Transfer, Lysine-Trna Ligase