Malarial Dihydrofolate Reductase as Drug Target

From Proteopedia

Revision as of 09:02, 29 November 2012

Introduction

There are currently antimalarial drugs that target the malarial dihydrofolate reductase (DHFR) such as pyrimethamine and cycloguanil. However, the effectiveness of these drugs has decreased because of mutations in the enzyme that have led to drug resistance. Since these mutations are becoming much more prevalent in malaria cases, new research in drug development must now incorporates both the wild-type as well as the quadruple mutant DHFR from the Plasmodium falciparum malarial strain, the most common and lethal of the malaria species.^[1]

spinqualitylabelsall models Crystal structure of Wild-type PfDHFR-TS COMPLEXED WITH NADPH, dUMP AND PYRIMETHAMINE (PDB entry 3QGT) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Mutant, Drug Resistant PfDHFR The of PfDHFR has four : N51I, C59R, S108N, and I164L.[2] These mutations cause decreased binding affinities of inhibitors, a huge factor being steric clashing. For pyrimethamine and cycloguanil specifically, the N51I mutation greatly effects their ability to bind the enzyme due to the drugs' rigid chlorophenyl substituents. In an effort to mitigate the effect of the mutations, the commonly occurring quadruple mutant must be addressed in the research of new PfDHFR targeting drugs. A first step in this direction was to experiment with the drug , a 4,6-diamino-1,2-dihydro-1,3,5-triazine that, with its (2,4,5-trichlorophenoxy)propoxy side chain, addressed the steric clash that was subjected to with a Ser108Asn mutation. However further research with this drug was stopped because of its gastrointestinal toxicity in humans and low bioavailbility.[3] Wr99210 was significantly more basic than pyrimethamine, a pyrimidine and slightly acidic substance to match that of the gastrointestinal track, and thus was not readily absorbed in the intestines. When it was compared via in vitro and in vivo experiments to P65, a less basic compound with a 2,4-diaminopyrimidine scaffold, P65 was shown to have significantly higher absorption in vivo. Thus, P65 was chosen as the basis for more research and the later discussed drug, P218. Though Wr99210 was effective at getting deep into the mutant PfDHFR active site, its ineffectiveness as an oral drug would have made it unsuccessful. It was resolved that a 2,4-diaminopyrimidine anchor on a new drug would allow the steric hindrance found with pyrimethamine to be avoided by replacing its rigid chlorophenyl group. In addition to this anchor allowing deep binding into the active site of PfDHFR, the other end of the molecule, a carboxylate group, would form strong hydrogen bonds with the conserved Arg122. These parts combined led to the compound P218 shown below. [4]

P218 and Species Specificity

There are three regions of the DHFR active site that differ between and Plasmodium falciparum that allows a drug to target the PfDHFR specifically while not harming that of humans. One important such difference is an arginine at codon 122 in PfDHFR and 70 in humans. In P218, the side chain carboxylate forms hydrogen bonds with the residue but has no interaction with the .

^[5]

References

1. ↑ Somsak V, Uthaipibull C, Prommana P, Srichairatanakool S, Yuthavong Y, Kamchonwongpaisan S. Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening. Malar J. 2011 Oct 7;10:291. PMID: 21981896
2. ↑ Huang F, Tang L, Yang H, Zhou S, Liu H, Li J, Guo S. Molecular epidemiology of drug resistance markers of Plasmodium falciparum in Yunnan Province, China. Malar J. 2012 Jul 28;11:243. PMID: 22839209
3. ↑ Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E, Thongphanchang C, Taweechai S, Vanichtanankul J, Rattanajak R, Arwon U, Fantauzzi P, Yuvaniyama J, Charman WN, Matthews D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16823-8. Epub 2012 Oct 3. PMID:23035243. doi: 10.1073/pnas.1204556109.
4. ↑ Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E, Thongphanchang C, Taweechai S, Vanichtanankul J, Rattanajak R, Arwon U, Fantauzzi P, Yuvaniyama J, Charman WN, Matthews D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16823-8. Epub 2012 Oct 3. PMID:23035243. doi: 10.1073/pnas.1204556109.
5. ↑ Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E, Thongphanchang C, Taweechai S, Vanichtanankul J, Rattanajak R, Arwon U, Fantauzzi P, Yuvaniyama J, Charman WN, Matthews D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16823-8. Epub 2012 Oct 3. PMID:23035243. doi: 10.1073/pnas.1204556109.