ArticleProceedings of the National Academy of Sciences of the United States of America2015
Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Polyether antibiotics K-41A and K-41Am inhibit HIV-1 replication via suppressing the activities of HIV-1 reverse transcriptase and integrase.Archives of medical science : AMS · 2025Article
- An interaction network in the polymerase active site is a prerequisite for Watson-Crick base pairing in Pol γ.Science advances · 2024Article
- Synthesis and Evaluation of Prodrugs of α-Carboxy Nucleoside Phosphonates.The Journal of organic chemistry · 2022Article
- Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies.Viruses · 2022Review
- Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket - targeting P-pocket by fragment screening.Nature communications · 2021Article
- Application of Molecular Dynamics Simulations to the Design of Nucleotide Inhibitors Binding to Norovirus Polymerase.Journal of chemical information and modeling · 2020Article
- Evolving understanding of HIV-1 reverse transcriptase structure, function, inhibition, and resistance.Current opinion in structural biology · 2020Review
- Overview of Biologically Active Nucleoside Phosphonates.Frontiers in chemistry · 2020Review
- Structural Basis of HIV-1 Inhibition by Nucleotide-Competing Reverse Transcriptase Inhibitor INDOPY-1.Journal of medicinal chemistry · 2019Article
- Alpha-carboxynucleoside phosphonates: direct-acting inhibitors of viral DNA polymerases.Future medicinal chemistry · 2019Review
- Guanine α-carboxy nucleoside phosphonate (G-α-CNP) shows a different inhibitory kinetic profile against the DNA polymerases of human immunodeficiency virus (HIV) and herpes viruses.Biochemical pharmacology · 2017Article
- NMR structure of the HIV-1 reverse transcriptase thumb subdomain.Journal of biomolecular NMR · 2016Article
- Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase.Nucleic acids research · 2016Review
- Conformational States of HIV-1 Reverse Transcriptase for Nucleotide Incorporation vs Pyrophosphorolysis-Binding of Foscarnet.ACS chemical biology · 2016Article
- Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η.Nucleic acids research · 2016Article
- Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates.Organic & biomolecular chemistry · 2016Article
- Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates.Journal of medicinal chemistry · 2015Article
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
Abstract
Polymerases have a structurally highly conserved negatively charged amino acid motif that is strictly required for Mg(2+) cation-dependent catalytic incorporation of (d)NTP nucleotides into nucleic acids. Based on these characteristics, a nucleoside monophosphonate scaffold, α-carboxy nucleoside phosphonate (α-CNP), was designed that is recognized by a variety of polymerases. Kinetic, biochemical, and crystallographic studies with HIV-1 reverse transcriptase revealed that α-CNPs mimic the dNTP binding through a carboxylate oxygen, two phosphonate oxygens, and base-pairing with the template. In particular, the carboxyl oxygen of the α-CNP acts as the potential equivalent of the α-phosphate oxygen of dNTPs and two oxygens of the phosphonate group of the α-CNP chelate Mg(2+), mimicking the chelation by the β- and γ-phosphate oxygens of dNTPs. α-CNPs (i) do not require metabolic activation (phosphorylation), (ii) bind directly to the substrate-binding site, (iii) chelate one of the two active site Mg(2+) ions, and (iv) reversibly inhibit the polymerase catalytic activity without being incorporated into nucleic acids. In addition, α-CNPs were also found to selectively interact with regulatory (i.e., allosteric) Mg(2+)-dNTP-binding sites of nucleos(t)ide-metabolizing enzymes susceptible to metabolic regulation. α-CNPs represent an entirely novel and broad technological platform for the development of specific substrate active- or regulatory-site inhibitors with therapeutic potential.
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