3JSU

Quadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMP

Summary for 3JSU

• Entry DOI: 10.2210/pdb3jsu/pdb
• Related: 1J3I 1J3J 1J3K 3DG8 3DGA
• Descriptor: Dihydrofolate reductase-thymidylate synthase, 5-chloro-N~6~-(2,5-dimethoxybenzyl)quinazoline-2,4,6-triamine, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: rossmann fold, oxidoreductase, transferase
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 2
• Total formula weight: 146643.09

Authors

Chitnumsub, P.,Maneeruttanarungroj, C.,Kamchonwongpaisan, S.,Yuthavong, Y.,Diagana, T.T. (deposition date: 2009-09-11, release date: 2010-07-28, Last modification date: 2023-11-01)

Primary citation

Nzila, A.,Rottmann, M.,Chitnumsub, P.,Kiara, S.M.,Kamchonwongpaisan, S.,Maneeruttanarungroj, C.,Taweechai, S.,Yeung, B.K.,Goh, A.,Lakshminarayana, S.B.,Zou, B.,Wong, J.,Ma, N.L.,Weaver, M.,Keller, T.H.,Dartois, V.,Wittlin, S.,Brun, R.,Yuthavong, Y.,Diagana, T.T.
Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate
Antimicrob.Agents Chemother., 54:2603-2610, 2010

PubMed Abstract: Drug resistance against dihydrofolate reductase (DHFR) inhibitors-such as pyrimethamine (PM)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent.

PubMed: 20350951
DOI: 10.1128/AAC.01526-09

Experimental method

X-RAY DIFFRACTION (2.7 Å)