NDLI: Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target

Content Provider	PubMed Central
Author	Yuthavong, Yongyuth Tarnchompoo, Bongkoch Vilaivan, Tirayut Chitnumsub, Penchit Kamchonwongpaisan, Sumalee Charman, Susan A. Mclennan, Danielle N. White, Karen L. Vivas, Livia Bongard, Emily Thongphanchang, Chawanee Taweechai, Supannee Vanichtanankul, Jarunee Rattanajak, Roonglawan Arwon, Uthai Fantauzzi, Pascal Yuvaniyama, Jirundon Charman, William N. Matthews, David
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.
Related Links	http://dx.doi.org/10.1073/pnas.1204556109
Ending Page	16828
Page Count	6
Starting Page	16823
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	42
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-10-16
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.

Mechanisms of drug resistance in Ḻe̲i̲s̲ẖm̲a̲ṉi̲a̲ m̲a̲j̲o̲ṟ and the characterization of the drug-target, the bifunctional protein, thymidylate synthase-dihydrofolate reductase

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance

Alpha-pyridine nucleotides as substrates for a plasmid-specified dihydrofolate reductase.

Chemical and genetic validation of dihydrofolate reductase–thymidylate synthase as a drug target in African trypanosomes

Synthesis and biological screening of some pyridine derivatives as anti-malarial agents

Stable molecular transformation of Toxoplasma gondii: a selectable dihydrofolate reductase-thymidylate synthase marker based on drug-resistance mutations in malaria.

Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target

Similar Documents

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.

Mechanisms of drug resistance in Ḻe̲i̲s̲ẖm̲a̲ṉi̲a̲ m̲a̲j̲o̲ṟ and the characterization of the drug-target, the bifunctional protein, thymidylate synthase-dihydrofolate reductase

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance

Alpha-pyridine nucleotides as substrates for a plasmid-specified dihydrofolate reductase.

Chemical and genetic validation of dihydrofolate reductase–thymidylate synthase as a drug target in African trypanosomes

Synthesis and biological screening of some pyridine derivatives as anti-malarial agents

Stable molecular transformation of Toxoplasma gondii: a selectable dihydrofolate reductase-thymidylate synthase marker based on drug-resistance mutations in malaria.

Crystal structure of dihydrofolate reductase from Plasmodium vivax: Pyrimethamine displacement linked with mutation-induced resistance

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target