title: Evaluation of novel acyclic nucleoside phosphonates against human and animal gammaherpesviruses revealed an altered metabolism of cyclic prodrugs upon Epstein-Barr virus reactivation in P3HR-1 cells.
abstract: Acyclic nucleoside phosphonates (ANPs), such as (S)-1-[(3-hydroxy-2-phosphonomethoxy)propyl)]cytosine (HPMPC), are an important group of broad-spectrum antiviral agents with activity against DNA viruses. In this report, we present the in vitro potencies of novel ANPs against gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus (EBV), and three animal gammaherpesviruses. 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-3-deazaadenine (3-deaza-HPMPA), and their cyclic derivatives have emerged as highly potent antigammaherpesvirus agents. Interestingly, cyclic prodrugs of ANPs exhibited reduced activities against EBV strain P3HR-1, but not against EBV strain Akata. Cell culture metabolism studies with HPMPC and cyclic HPMPC revealed that these differences were attributable to an altered drug metabolism in P3HR-1 cells after EBV reactivation and, more specifically, to a reduced hydrolysis of cyclic HPMPC by cyclic CMP phosphodiesterase. We did not correlate this effect with phosphodiesterase downregulation, or to functional mutations. Instead, altered cyclic AMP levels in P3HR-1 cells indicated a competitive inhibition of the phosphodiesterase by this cyclic nucleotide. Finally, both HPMPC and HPMP-5-azaC emerged as highly effective inhibitors in vivo through significant inhibition of murine gammaherpesvirus replication and dissemination. With the current need for potent antigammaherpesvirus agents, our findings underline the requirement of appropriate surrogate viruses for antiviral susceptibility testing and highlight HPMP-5-azaC as a promising compound for future clinical development.
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Natacha
authors.initials: N
authors.lastname: Coen
authors.forename: Sophie
authors.initials: S
authors.lastname: Duraffour
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Marcela
authors.initials: M
authors.lastname: Krecmerová
authors.forename: Joost
authors.initials: J
authors.lastname: Van den Oord
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D000077404:Cidofovir; D000242:Cyclic AMP / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018142:Gammaherpesvirinae / Q000187:drug effects*; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000821:virology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D063065:Organophosphonates / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D014412:Tumor Virus Infections / Q000188:drug therapy* / Q000821:virology; D014775:Virus Activation / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C072572:cyclic-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; C039854:5-azacytosine; D003596:Cytosine; D000242:Cyclic AMP; D000077404:Cidofovir
references.citation: Cancer Lett. 2011 Jun 28;305(2):163-74
references.pmid: 21493001
references.citation: Antimicrob Agents Chemother. 1998 Jan;42(1):170-2
references.pmid: 9449280
references.citation: Methods Mol Med. 2000;24:139-50
references.pmid: 21331906
references.citation: J Virol. 1996 Nov;70(11):8151-4
references.pmid: 8892944
references.citation: Biochem Pharmacol. 2008 Oct 15;76(8):997-1005
references.pmid: 18773877
references.citation: PLoS Pathog. 2009 Oct;5(10):e1000606
references.pmid: 19798430
references.citation: J Virol. 2000 Sep;74(17):8166-75
references.pmid: 10933728
references.citation: J Antimicrob Chemother. 2005 Aug;56(2):277-81
references.pmid: 16006448
references.citation: J Virol. 2004 Feb;78(4):1893-902
references.pmid: 14747554
references.citation: Biochem Pharmacol. 2011 Jul 15;82(2):99-109
references.pmid: 21501598
references.citation: J Biol Chem. 2000 Sep 29;275(39):30069-74
references.pmid: 10893247
references.citation: J Clin Virol. 2010 Nov;49(3):151-7
references.pmid: 20739216
references.citation: Virol J. 2006 Jun 06;3:43
references.pmid: 16756670
references.citation: Eur J Biochem. 1991 Jan 1;195(1):9-27
references.pmid: 1846812
references.citation: Br J Pharmacol. 1998 Mar;123(6):1031-8
references.pmid: 9559883
references.citation: Antimicrob Agents Chemother. 1997 Dec;41(12):2754-6
references.pmid: 9420052
references.citation: J Med Chem. 2007 Mar 8;50(5):1069-77
references.pmid: 17298047
references.citation: J Virol. 2002 Oct;76(19):9819-31
references.pmid: 12208960
references.citation: Am J Transplant. 2013 Feb;13 Suppl 3:41-54; quiz 54
references.pmid: 23347213
references.citation: J Virol. 2013 Apr;87(7):3839-51
references.pmid: 23345517
references.citation: Nat Rev Microbiol. 2004 Aug;2(8):656-68
references.pmid: 15263900
references.citation: Acta Virol. 2013;57(2):105-12
references.pmid: 23600868
references.citation: Mol Pharmacol. 1996 Dec;50(6):1502-10
references.pmid: 8967971
references.citation: Cancer Res. 2001 Nov 1;61(21):7875-7
references.pmid: 11691806
references.citation: Nat Rev Drug Discov. 2005 Nov;4(11):928-40
references.pmid: 16264436
references.citation: J Biol Chem. 2003 May 16;278(20):17664-71
references.pmid: 12637526
references.citation: Antiviral Res. 1987 Dec;8(5-6):261-72
references.pmid: 3451698
references.citation: J Virol. 2007 Mar;81(6):2957-69
references.pmid: 17215283
references.citation: Antivir Chem Chemother. 1998 May;9(3):275-82
references.pmid: 9875407
references.citation: Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):331-41
references.pmid: 16247948
references.citation: Antiviral Res. 2004 Jun;62(3):121-3
references.pmid: 15130535
references.citation: Infect Immun. 1977 Nov;18(2):342-7
references.pmid: 200559
references.citation: Antimicrob Agents Chemother. 1987 Sep;31(9):1431-3
references.pmid: 2823699
references.citation: Antimicrob Agents Chemother. 1991 Nov;35(11):2440-3
references.pmid: 1666500
references.citation: Antimicrob Agents Chemother. 1999 Feb;43(2):271-7
references.pmid: 9925517
references.citation: J Infect Dis. 2007 Oct 15;196(8):1163-6
references.pmid: 17955434
references.citation: Clin Microbiol Rev. 2010 Apr;23(2):350-66
references.pmid: 20375356
references.citation: Antimicrob Agents Chemother. 1997 Mar;41(3):641-6
references.pmid: 9056007
references.citation: Cancer Res. 1998 Feb 1;58(3):384-8
references.pmid: 9458076
references.citation: J Immunol. 1990 Jun 15;144(12):4788-93
references.pmid: 2161880
references.citation: J Virol. 1997 Jan;71(1):314-24
references.pmid: 8985352
references.citation: Curr Opin Hematol. 2012 Jan;19(1):14-20
references.pmid: 22123662
references.citation: Virology. 1992 Jun;188(2):916-20
references.pmid: 1316687
references.citation: J Virol. 2013 May;87(9):5311-5
references.pmid: 23449792
references.citation: Antivir Chem Chemother. 1999 Nov;10(6):321-6
references.pmid: 10628807