ArticleProceedings of the National Academy of Sciences of the United States of America2012
Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
98 citing papers in PubMed, 275 citations in OpenAlex.
- Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.British journal of clinical pharmacology · 2022Trial
- First-in-human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection.British journal of clinical pharmacology · 2020Trial
- Searching for new candidates for antimalarial therapy: physicochemical and in vitro evaluation of gold(I) and silver(I) N-heterocyclic carbene complexes.Malaria journal · 2026Article
- Bisubstrate Analog Inhibitors of DXP Synthase Show Species Specificity.Biochemistry · 2025Article
- Targeting Malaria's Achilles' Heels: A Review of Plasmodium Life Cycle Vulnerabilities for Drug Discovery.Current topics in medicinal chemistry · 2025Review
- The possibilities and challenges associated with selective targetingTransactions of the Royal Society of South Africa. Royal Society of South Africa · 2025Article
- To quest new targets ofJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2024Review
- Screening the Global Health Priority Box against Plasmodium berghei liver stage parasites using an inexpensive luciferase detection protocol.Malaria journal · 2024Article
- Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active againstJournal of medicinal chemistry · 2024Article
- Computational approach for decoding malaria drug targets from single-cell transcriptomics and finding potential drug molecule.Scientific reports · 2024Article
- Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Novel flexible biphenylRSC medicinal chemistry · 2024Article
- Combating antimicrobial resistance in malaria, HIV and tuberculosis.Nature reviews. Drug discovery · 2024Review
- Genetic complexity alters drug susceptibility of asexual and gametocyte stages ofAntimicrobial agents and chemotherapy · 2024Article
- Article
- Single-cell quantitative bioimaging ofmSphere · 2023Article
- Mapping the genomic landscape of multidrug resistance inScience advances · 2023Article
- In Silico Studies of Four Compounds ofMolecules (Basel, Switzerland) · 2023Article
- Discovery of rigid biphenylRSC medicinal chemistry · 2023Article
- Novel Therapeutics for Malaria.Pharmaceutics · 2023Review
38 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 8 institutions in 4 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.