ArticleAntimicrobial agents and chemotherapy2010
Stereoselective phosphorylation of cyclopropavir by pUL97 and competitive inhibition by maribavir.
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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
28 citing papers in PubMed, 39 citations in OpenAlex.
- Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers.Antimicrobial agents and chemotherapy · 2019Trial
- Article
- Anti-CMV therapy, what next? A systematic review.Frontiers in microbiology · 2023Review
- Pentostatin antagonizes the antiviral activity of MBX-2168 by inhibiting the biosynthesis of the active compound.Antiviral research · 2021Article
- Antiviral Drugs Against Herpesviruses.Advances in experimental medicine and biology · 2021Article
- Early diagnosis and successful treatment of cytomegalovirus peritonitis in children with primary nephrotic syndrome: case series and literature review.Renal failure · 2020Review
- Filociclovir Is a PotentAntimicrobial agents and chemotherapy · 2020Article
- Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy.Current hematologic malignancy reports · 2020Review
- Advances in the Development of Therapeutics for Cytomegalovirus Infections.The Journal of infectious diseases · 2020Review
- Biosynthesis and half-life of MBX-2168-triphosphate in herpes virus-infected cells.Antiviral research · 2020Article
- Activation of 6-Alkoxy-Substituted Methylenecyclopropane Nucleoside Analogs Requires Enzymatic Modification by Adenosine Deaminase-Like Protein 1.Antimicrobial agents and chemotherapy · 2019Article
- Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase.Nucleic acids research · 2016Review
- Potency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase.Antimicrobial agents and chemotherapy · 2016Article
- Antagonistic Relationship between Human Cytomegalovirus pUL27 and pUL97 Activities during Infection.Journal of virology · 2015Article
- TAOK3 phosphorylates the methylenecyclopropane nucleoside MBX 2168 to its monophosphate.Antiviral research · 2015Article
- Current and potential treatments for ubiquitous but neglected herpesvirus infections.Chemical reviews · 2014Review
- Review
- Human cytomegalovirus UL97 kinase is involved in the mechanism of action of methylenecyclopropane analogs with 6-ether and -thioether substitutions.Antimicrobial agents and chemotherapy · 2014Article
- Metabolism of cyclopropavir and ganciclovir in human cytomegalovirus-infected cells.Antimicrobial agents and chemotherapy · 2014Article
- Highlights in antiviral drug research: antivirals at the horizon.Medicinal research reviews · 2013Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Human cytomegalovirus (HCMV) is a widespread pathogen that can cause severe disease in immunologically immature and immunocompromised individuals. Cyclopropavir (CPV) is a guanine nucleoside analog active against human and murine cytomegaloviruses in cell culture and efficacious in mice by oral administration. Previous studies established that the mechanism of action of CPV involves inhibition of viral DNA synthesis. Based upon this action and the structural similarity of CPV to ganciclovir (GCV), we hypothesized that CPV must be phosphorylated to a triphosphate to inhibit HCMV DNA synthesis and that pUL97 is the enzyme responsible for the initial phosphorylation of CPV to a monophosphate (CPV-MP). We found that purified pUL97 phosphorylated CPV 45-fold more extensively than GCV, a known pUL97 substrate and the current standard of treatment for HCMV infections. Kinetic studies with CPV as the substrate for pUL97 demonstrated a Km of 1,750+/-210 microM. Introduction of 1.0 or 10 nM maribavir, a known pUL97 inhibitor, and subsequent Lineweaver-Burk analysis demonstrated competitive inhibition of CPV phosphorylation, with a Ki of 3.0+/-0.3 nM. Incubation of CPV with pUL97 combined with GMP kinase [known to preferentially phosphorylate the (+)-enantiomer of CPV-MP] established that pUL97 stereoselectively phosphorylates CPV to its (+)-monophosphate. These results elucidate the mechanism of CPV phosphorylation and help explain its selective antiviral action.
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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.