Document Detail


Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.
MedLine Citation:
PMID:  23035243     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-17     Completed Date:  2012-12-31     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16823-8     Citation Subset:  IM    
Affiliation:
BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand. yongyuth@biotec.or.th
Data Bank Information
Bank Name/Acc. No.:
PDB/4DDR;  4DP3;  4DPD;  4DPH
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimalarials / chemistry*,  pharmacokinetics,  pharmacology*
Catalytic Domain / genetics
Crystallography, X-Ray
Drug Design
Folic Acid Antagonists / metabolism*
Mice
Mice, SCID
Models, Molecular*
Molecular Structure
Plasmodium falciparum / enzymology*
Protein Conformation
Tetrahydrofolate Dehydrogenase / chemistry*,  metabolism*
Grant Support
ID/Acronym/Agency:
//Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Antimalarials; 0/Folic Acid Antagonists; EC 1.5.1.3/Tetrahydrofolate Dehydrogenase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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