1. Conservation of antiviral activity and improved selectivity in PMEO-DAPym upon pyrimidine to triazine scaffold hopping
- Author
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Federico Gago, María-José Camarasa, Graciela Andrei, Jan Balzarini, Brent E. Korba, Robert Snoeck, Gloria Fernández-Cureses, Pedro A. Sánchez-Murcia, Sonia de Castro, Comunidad de Madrid, University of Leuven, Ministerio de Ciencia e Innovación (España), and Ministerio de Economía y Competitividad (España)
- Subjects
Models, Molecular ,Pyrimidine ,Anti-HIV Agents ,Herpesvirus 2, Human ,viruses ,Organophosphonates ,Herpesvirus 1, Human ,medicine.disease_cause ,Antiviral Agents ,Herpesviridae ,Nucleobase ,Sarcoma Viruses, Murine ,chemistry.chemical_compound ,Virology ,medicine ,Humans ,Secretion ,Cells, Cultured ,Polymerase ,Triazine ,Pharmacology ,biology ,Triazines ,Active site ,Nucleosides ,Pyrimidines ,Biochemistry ,chemistry ,Chemokines, CC ,Viruses ,HIV-1 ,Leukocytes, Mononuclear ,biology.protein ,Selectivity - Abstract
Acyclic nucleoside phosphonates incorporating 2,4-diaminotriazine (DAT) as a 5-aza-analog of the 2,4-diamino-pyrimidine (DAPym) nucleobase present in PMEO-DAPyms have been synthesized. The lead PMEO-DAT is as inhibitory against HIV, HBV, MSV and VZV replication as the parent PMEO-DAPym and equally inefficient at markedly affecting replication of HSV-1, HSV-2 and HCMV. A rationale for this similar biological profile is proposed on the basis of structural differences in the active site of the viral DNA polymerases. PMEO-DAT is, however, more selective because, unlike PMEO-DAPym, it does not stimulate secretion of β-chemokines in cultured PBMC., S.d.C. thanks the Spanish MICINN for a post-doctoral Juan de la Cierva contract (JDC-MICINN). We also thank the Spanish MINECO (SAF2012-39760-C02), Comunidad de Madrid (BIPEDD-2-CM S-2010/BMD-2457), and KU Leuven (GOA No. 10/014) for financial support, and Mrs. Lizette van Berckelaer, Mrs. Leen Ingels, Mrs. Leentje Persoons, Mrs. Frieda De Meyer, Mrs. Anita Camps, Mrs. Lies Van den Heurck, Mr. Steven Carmans and Mrs. Sandra Claes for dedicated technical assistance.
- Published
- 2015