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Title: Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
Authors: Yongyuth Yuthavong
Bongkoch Tarnchompoo
Tirayut Vilaivan
Penchit Chitnumsub
Sumalee Kamchonwongpaisan
Susan A. Charman
Danielle N. McLennan
Karen L. White
Livia Vivas
Emily Bongard
Chawanee Thongphanchang
Supannee Taweechai
Jarunee Vanichtanankul
Roonglawan Rattanajak
Uthai Arwon
Pascal Fantauzzi
Jirundon Yuvaniyama
William N. Charman
David Matthews
Thailand National Center for Genetic Engineering and Biotechnology
Chulalongkorn University
Monash University
London School of Hygiene & Tropical Medicine
Medicines for Malaria Venture
Mahidol University
Keywords: Multidisciplinary
Issue Date: 16-Oct-2012
Citation: Proceedings of the National Academy of Sciences of the United States of America. Vol.109, No.42 (2012), 16823-16828
Abstract: Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.
ISSN: 10916490
Appears in Collections:Scopus 2011-2015

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