Anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)-cycloprop-1'-yl]methyl] x guanine (A-5021) in vitro and in vivo.
The novel nucleoside analog (1S',2R')-9-[[1',2'-bis(hydroxymethyl)cycloprop-1-yl]methyl]guanine (A-5021) was previously shown to be a potent inhibitor of the replication of herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and varicella zoster virus (VZV), both in vitro and in vivo (J. Med. Chem. 41, 1284-1298; Antimicrob. Agents Chemother. 42, 1666-1670). Here we demonstrate that A-5021 is also a potent inhibitor of Epstein-Barr virus (EBV) and human herpes virus 6 (HHV-6A and HHV-6B), but that the compound lacks activity against HHV-8. A-5021, in comparison to acyclovir, was also assessed for protective activity against HSV-1-induced mortality in SCID mice. The compounds were administered at 50 mg/kg per day by subcutaneous injection for four consecutive days and treatment was initiated at either 2 h, 1 or 2 days post infection (p.i.). When administered from day 0 to 4 p.i., A-5021 conferred complete protection against the infection (as assessed at 22 days p.i.), whereas acyclovir delayed virus induced mortality by only 5 days. When treatment was begun on day 1 or 2, A-5021 still afforded marked protection against the infection, whereas acyclovir was virtually devoid of any activity under these conditions. Our data underline that A-5021 may offer great promise for the treatment of herpesvirus infections.
Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium. johan.neyts@rega.kuleuven.ac.jp
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Neyts
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Naesens
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Ying
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De Bolle
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De Clercq
D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology; D006564:Herpesviridae / Q000187:drug effects*; D006566:Herpesviridae Infections / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID
C111645:9-((cis-1,2-bis(hydroxymethyl)cycloprop-1-yl)methyl)guanine; D000998:Antiviral Agents; D006147:Guanine; D000212:Acyclovir