A series of nonnucleoside, N-␣-methylbenzyl-N-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target. Sequencing of the VZV ORF54 gene from two independently derived resistant viruses revealed mutations in ORF54 compared to the parental VZV strain Ellen sequence. Recombinant VZV in which the wild-type ORF54 sequence was replaced with the ORF54 gene from either of the resistant viruses became resistant to the series of inhibitor compounds. Treatment of VZV-infected cells with the inhibitor impaired morphogenesis of capsids. Inhibitor-treated cells lacked DNA-containing dense-core capsids in the nucleus, and only incomplete virions were present on the cell surface. These data suggest that the VZV-specific thiourea inhibitor series block virus replication by interfering with the function of the ORF54 protein and/or other proteins that interact with the ORF54 protein.Varicella-zoster virus (VZV) causes a disseminated primary infection, chickenpox, and later may reactivate to cause herpes zoster, commonly known as shingles (3,26). Herpes zoster can result in pain lasting over 1 month from the onset of the rash, termed postherpetic neuralgia (PHN). PHN is often a debilitating condition that is quite difficult to treat (15,32,33).Acyclovir (ACV), valaciclovir, and famciclovir are the primary antivirals used for treating VZV infections in both immunocompetent and immunocompromised individuals (25). Unfortunately, despite these medications, PHN remains a major problem, and the currently available drugs have a limited effect on prevention of this condition. Thus, there is a need for additional, more effective medications to treat herpes zoster in adults.The development of antiviral resistance remains a concern, particularly when treatment relies on only a small number of approved drugs with common modes of action (13,14,25,26). ACV, valaciclovir (which is metabolized to acyclovir), and famciclovir (the prodrug of penciclovir) are all phosphorylated by the viral thymidine kinase as an initial step for intracellular activation. They are subsequently phosphorylated by cellular kinases, and the activated compounds inhibit the viral DNA polymerase. Sorivudine and brivudine are also potent inhibitors of VZV, and although they represent a different class of nucleoside analogues from ACV, they also require phosphorylation by the viral thymidine kinase for activation (18,31). While thymidine kinase-deficient VZV can be treated with foscarnet, a direct inhibitor of the viral DNA polymerase (25), this drug requires intravenous administration and has a marked potential for...

Several compounds that specifically inhibited replication of the H1 and H2 subtypes of influenza virus type A were identified by screening a chemical library for antiviral activity. In single-cycle infections, the compounds inhibited virus-specific protein synthesis when added before or immediately after infection but were ineffective when added 30 min later, suggesting that an uncoating step was blocked. Sequencing of hemagglutinin (HA) genes of several independent mutant viruses resistant to the compounds revealed single amino acid changes that clustered in the stem region of the HA trimer in and near the HA2 fusion peptide. One of the compounds, an N-substituted piperidine, could be docked in a pocket in this region by computer-assisted molecular modeling. This compound blocked the fusogenic activity of HA, as evidenced by its inhibition of low-pH-induced cell-cell fusion in infected cell monolayers. An analog which was more effective than the parent compound in inhibiting virus replication was synthesized. It was also more effective in blocking other manifestations of the low-pH-induced conformational change in HA, including virus inactivation, virus-induced hemolysis of erythrocytes, and susceptibility of the HA to proteolytic degradation. Both compounds inhibited viral protein synthesis and replication more effectively in cells infected with a virus mutated in its M2 protein than with wild-type virus. The possible functional relationship between M2 and HA suggested by these results is discussed.

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