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Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis.

  • Jain V Molecular Medicine - Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India.
  • Yogavel M Molecular Medicine - Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India.
  • Kikuchi H Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama Aoba-ku, Sendai 980-8578, Japan.
  • Oshima Y Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama Aoba-ku, Sendai 980-8578, Japan.
  • Hariguchi N Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10, Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
  • Matsumoto M Pharmaceutical Business Division, Otsuka Pharmaceutical Co., Ltd., 463-10, Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
  • Goel P Molecular Medicine - Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India.
  • Touquet B Institute for Advanced Biosciences (IAB), CNRS UMR5309, INSERM U1209, Grenoble Alpes University, 38000 Grenoble, France.
  • Jumani RS Department of Medicine, and Cell, Molecular, and Biomedical Sciences Graduate Program, University of Vermont College of Medicine, Burlington, VT 05405, USA.
  • Tacchini-Cottier F Department of Biochemistry, WHO-IRTC, University of Lausanne, Lausanne 1066, Switzerland.
  • Harlos K Division of Structural Biology, Wellcome Trust Centre for Human Genetics, The Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
  • Huston CD Department of Medicine, and Cell, Molecular, and Biomedical Sciences Graduate Program, University of Vermont College of Medicine, Burlington, VT 05405, USA.
  • Hakimi MA Institute for Advanced Biosciences (IAB), CNRS UMR5309, INSERM U1209, Grenoble Alpes University, 38000 Grenoble, France.
  • Sharma A Molecular Medicine - Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India. Electronic address: amitpsharma68@gmail.com.
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  • 2017-09-05
Published in:
  • Structure (London, England : 1993). - 2017
X-ray crystallography
coccidiosis
cryptosporidiosis
drug discovery
leishmaniasis
malaria
prolyl-tRNA synthetase
toxoplasmosis
Amino Acyl-tRNA Synthetases
Animals
Catalytic Domain
Coccidiosis
Cryptosporidiosis
Drug Discovery
Enzyme Inhibitors
Humans
Leishmaniasis
Malaria
Mice
Models, Molecular
Protozoan Infections
Protozoan Proteins
Quinazolinones
Structure-Activity Relationship
Toxoplasmosis
English Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/106229
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