Publication: Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
2
Issued Date
2012-10-16
Resource Type
ISSN
10916490
00278424
00278424
Other identifier(s)
2-s2.0-84867653932
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Mahidol University
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SCOPUS
Bibliographic Citation
Proceedings of the National Academy of Sciences of the United States of America. Vol.109, No.42 (2012), 16823-16828
Suggested Citation
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 Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proceedings of the National Academy of Sciences of the United States of America. Vol.109, No.42 (2012), 16823-16828. doi:10.1073/pnas.1204556109 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/15238
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Title
Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target
Author(s)
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
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
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.