In vitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpesvirus replication.
We have reported previously that methylenecyclopropane analogs of nucleosides have excellent activity against certain members of the herpesvirus family. A second generation, the 2,2-bis-hydroxymethyl derivatives, were synthesized, and 18 compounds were tested for activity in vitro against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human and murine cytomegalovirus (HCMV and MCMV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). Selected analogs were also evaluated against human herpesvirus type 6 (HHV-6) and HHV-8. None of the 18 compounds had activity against HSV-1 or HSV-2, but four were active against VZV by plaque reduction (PR) assay at 50% effective concentration (EC(50)) levels of < or =50 microM. Six of the 18 compounds were active against HCMV by cytopathic effect or PR assays with EC(50)s of 0.5 to 44 microM, and all were active against MCMV by PR (0.3 to 54 microM). Four of the compounds were active against EBV by enzyme-linked immunosorbent assay (<0.3 to 4.4 microM). Four compounds with CMV activity were also active against HHV-6A and HHV-6B (0.7 to 28 microM), and three compounds were active against HHV-8 (5.5 to 16 microM). One of these, ZSM-I-62, had particularly good activity against CMV, HHV-6, and HHV-8, with EC(50)s of 0.7 to 8 microM. Toxicity was evaluated in adherent and nonadherent cells, and minimal cytotoxicity was observed. Mechanism of action studies with HCMV suggested that these compounds are phosphorylated by the ppUL97 phosphotransferase and are potent inhibitors of viral DNA synthesis. These results indicate that at least one of these compounds may have potential for use in treating CMV and other herpesvirus infections in humans.
Kern
Earl R
ER
The University of Alabama at Birmingham, Department of Pediatrics, 128 Children's Harbor Building, 1600 6th Ave. South, Birmingham, AL 35233, USA. kern@uab.edu
Kushner
Nicole L
NL
Hartline
Caroll B
CB
Williams-Aziz
Stephanie L
SL
Harden
Emma A
EA
Zhou
Shaoman
S
Zemlicka
Jiri
J
Prichard
Mark N
MN
D000998:Antiviral Agents / Q000494:pharmacology*; D015774:Ganciclovir / Q000494:pharmacology; D006564:Herpesviridae / Q000187:drug effects* / Q000502:physiology; D009705:Nucleosides / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D009705:Nucleosides; D015774:Ganciclovir
Antiviral Res. 1990 Oct-Nov;14(4-5):181-205
2088205
J Infect Dis. 1973 Sep;128(3):290-9
4353930
J Med Chem. 1998 Jan 1;41(1):10-23
9438017
Antivir Chem Chemother. 1998 Jul;9(4):341-52
9875413
J Virol. 1999 Jul;73(7):5663-70
10364316
Antiviral Res. 1999 Aug;43(1):37-53
10480262
Antimicrob Agents Chemother. 2004 Dec;48(12):4745-53
15561852
Antiviral Res. 1999 Oct;43(3):175-88
10551375
Antimicrob Agents Chemother. 2000 Jun;44(6):1506-11
10817700
Antivir Chem Chemother. 2000 May;11(3):191-202
10901290
J Infect Dis. 2001 Dec 15;184(12):1598-602
11740736
Antimicrob Agents Chemother. 2002 Aug;46(8):2365-72
12121906
Antiviral Res. 2002 Dec;56(3):273-8
12406510
J Med Chem. 2003 Apr 10;46(8):1531-7
12672254
Antiviral Res. 2003 Apr;58(2):149-57
12742575
Pharmacol Ther. 2003 Jun;98(3):269-97
12782241
Antimicrob Agents Chemother. 2003 Jul;47(7):2186-92
12821466
J Infect Dis. 2003 Jul 1;188(1):32-9
12825168
Nucleosides Nucleotides Nucleic Acids. 2003 Dec;22(12):2105-19
14714760
J Med Chem. 2004 Jan 29;47(3):566-75
14736238
J Virol. 1996 May;70(5):3018-25
8627778