Activity and mechanism of action of HDVD, a novel pyrimidine nucleoside derivative with high levels of selectivity and potency against gammaherpesviruses.
A novel nucleoside analogue, 1-[(2S,4S-2-(hydroxymethyl)-1,3-dioxolan-4-yl]5-vinylpyrimidine-2,4(1H,3H)-dione, or HDVD, was evaluated against a wide variety of herpesviruses and was found to be a highly selective inhibitor of replication of the gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). HDVD had also a pronounced inhibitory activity against murine herpesvirus 68 (MHV-68) and herpes simplex virus 1 (HSV-1). In contrast, replication of herpesvirus saimiri (HVS), HSV-2, and varicella-zoster virus (VZV) was weakly inhibited by the compound, and no antiviral activity was determined against human cytomegalovirus (HCMV) and rhesus rhadinovirus (RRV). The HDVD-resistant virus phenotype contained point mutations in the viral thymidine kinase (TK) of HSV-1, MHV-68, and HVS isolates. These mutations conferred cross-resistance to other TK-dependent drugs, with the exception of an MHV-68 mutant (E358D) that exhibited resistance only to HDVD. HSV-1 and HVS TK-mutants isolated under selective pressure with bromovinyldeoxyuridine (BVDU) also showed reduced sensitivity to HDVD. Oral treatment with HDVD and BVDU was assessed in an intranasal model of MHV-68 infection in BALB/c mice. In contrast to BVDU treatment, HDVD-treated animals showed a reduction in viral DNA loads and diminished viral gene expression during acute viral replication in the lungs in comparison to levels in untreated controls. The valyl ester prodrug of HDVD (USS-02-71-44) suppressed the latent infection in the spleen to a greater extent than HDVD. In the present study, HDVD emerged as a highly potent antiviral with a unique spectrum of activity against herpesviruses, in particular, gammaherpesviruses, and may be of interest in the treatment of virus-associated diseases.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
N
N
Coen
U
U
Singh
V
V
Vuyyuru
J J
JJ
Van den Oord
J
J
Balzarini
S
S
Duraffour
R
R
Snoeck
Y C
YC
Cheng
C K
CK
Chu
G
G
Andrei
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D016645:Aotidae; D017931:DNA Primers / Q000235:genetics; D005347:Fibroblasts; D018142:Gammaherpesvirinae / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018144:Rhadinovirus / Q000187:drug effects; D013045:Species Specificity; D018709:Statistics, Nonparametric; D013937:Thymidine Kinase / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
C580827:1-(2-(hydroxymethyl)-1,3-dioxolan-4-yl)5-vinylpyrimidine-2,4(1H,3H)-dione; D000998:Antiviral Agents; D017931:DNA Primers; D009705:Nucleosides; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines; D013937:Thymidine Kinase; C030986:pyrimidine