title: Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis.
abstract: The Chinese herb Dichroa febrifuga has traditionally treated malaria-associated fever. Its active component febrifugine (FF) and derivatives such as halofuginone (HF) are potent anti-malarials. Here, we show that FF-based derivatives arrest parasite growth by direct interaction with and inhibition of the protein translation enzyme prolyl-tRNA synthetase (PRS). Dual administration of inhibitors that target different tRNA synthetases suggests high utility of these drug targets. We reveal the ternary complex structure of PRS-HF and adenosine 5'-(β,γ-imido)triphosphate where the latter facilitates HF integration into the PRS active site. Structural analyses also highlight spaces within the PRS architecture for HF derivatization of its quinazolinone, but not piperidine, moiety. We also show a remarkable ability of HF to kill the related human parasite Toxoplasma gondii, suggesting wider HF efficacy against parasitic PRSs. Hence, our cell-, enzyme-, and structure-based data on FF-based inhibitors strengthen the case for their inclusion in anti-malarial and anti-toxoplasmosis drug development efforts.
authors: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors: Vitul
authors: V
authors: Jain
authors: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors: Manickam
authors: M
authors: Yogavel
authors: Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama Aoba-ku, Sendai 980-8578, Japan.
authors: Yoshiteru
authors: Y
authors: Oshima
authors: Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama Aoba-ku, Sendai 980-8578, Japan.
authors: Haruhisa
authors: H
authors: Kikuchi
authors: CNRS, UMR5163, LAPM, 38041 Grenoble, France; Université Joseph Fourier, 38000 Grenoble, France.
authors: Bastien
authors: B
authors: Touquet
authors: CNRS, UMR5163, LAPM, 38041 Grenoble, France; Université Joseph Fourier, 38000 Grenoble, France.
authors: Mohamed-Ali
authors: MA
authors: Hakimi
authors: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India. Electronic address: amit.icgeb@gmail.com.
authors: Amit
authors: A
authors: Sharma
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry* / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D003461:Crystallography; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology
chemical_list: D000962:Antimalarials; D046912:Multiprotein Complexes; D010880:Piperidines; D015800:Protozoan Proteins; D052999:Quinazolinones; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase; C010176:halofuginone