Conservation of antiviral activity and improved selectivity in PMEO-DAPym upon pyrimidine to triazine scaffold hopping.
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.
Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
Sonia
S
de Castro
Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
Gloria
G
Fernández-Cureses
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Graciela
G
Andrei
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Robert
R
Snoeck
Department of Biomedical Sciences, University of Alcalá, Unidad Asociada CSIC, E-28871 Alcalá de Henares, Madrid, Spain.
Pedro A
PA
Sánchez-Murcia
Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Road, Medical-Dental Building, Washington, DC 200057, United States.
Brent
B
Korba
Department of Biomedical Sciences, University of Alcalá, Unidad Asociada CSIC, E-28871 Alcalá de Henares, Madrid, Spain.
Federico
F
Gago
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Jan
J
Balzarini
Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain. Electronic address: mj.camarasa@iqm.csic.es.
María-José
MJ
Camarasa
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006564:Herpesviridae / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008958:Models, Molecular; D009705:Nucleosides; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D009053:Sarcoma Viruses, Murine / Q000187:drug effects*; D014227:Triazines / Q000737:chemistry; D014780:Viruses / Q000187:drug effects
C586406:6-phosphonylmethoxyethoxy-2,4-diaminopyrimidine; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D019742:Chemokines, CC; D009705:Nucleosides; D063065:Organophosphonates; D011743:Pyrimidines; D014227:Triazines; C030986:pyrimidine
Antivirals; Phosphonates; Polymerase inhibitors; Scaffold hopping; Triazine