Herpes Simplex Virus Type 1 Entry Is Inhibited by the Cobalt Chelate Complex CTC-96

Abstract

The CTC series of cobalt chelates display in vitro and in vivo activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). The experiments described here identify the stage in the virus life cycle where CTC-96 acts and demonstrate that the drug inhibits infection of susceptible cells. CTC-96 at 50 g/ml has no effect on adsorption of virions to Vero cell monolayers. Penetration assays reveal that CTC-96 inhibits entry of the virus independent of gC and cellular entry receptors. This observation was supported by the failure to detect the accumulation of virus-specified proteins and ␣ mRNA transcripts when CTC-96 is present at the onset of infection. Moreover, virion-associated ␣TIF does not accumulate in the nucleus of cells infected in the presence of CTC-96. CTC-96 targets the initial fusion event between the virus and the cell and also inhibits cell-to-cell spread and syncytium formation. Furthermore, CTC-96 inhibits plaque formation by varicellazoster virus and vesicular stomatitis virus as efficiently as by HSV-1. Collectively, these experiments suggest that CTC-96 is a broad-spectrum inhibitor of infection by enveloped viruses and that it inhibits HSV-1 infection at the point of membrane fusion independent of the type of virus and cellular receptors present.Infection by the alphaherpesviruses herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) results in a variety of viral diseases including oral and genital epithelial lesions, encephalitis, and ocular keratitis (15,16,20,96,103). Among these, herpetic ocular infection is the leading infectious cause of blindness in developed countries (48,55,56,96). Herpesvirus infections are characterized by their ability to establish latency and reactivate from the latent state (80). In immunocompetent and immunocompromised patients herpesvirus infections are among the most frequent causes of viral disease (78,93,104). Both primary and recrudescent infections in immunocompromised patients are life threatening (78,93,104). Thus, there exists considerable interest in developing treatments for preventing infection and reducing the pathogenesis of primary and recurrent infections by HSV.Several nucleoside analogs are approved for use in the treatment of herpesvirus infections (e.g., acyclovir, penciclovir, valaciclovir, and famciclovir), and derivatives of these are being developed and/or are undergoing clinical trials (2, 5, 17). These drugs are activated by the HSV thymidine kinase, and thus their primary target is virus DNA synthesis (26, 32). Not surprisingly, drug-resistant strains are appearing with increasing frequency (13,14,17,28,29,54,70,85). Resistance arises from mutations in the TK gene (18,27) or mutations in the gene encoding DNA polymerase (13,14,47,70,85). Therefore, new drugs need to be developed that target other aspects of the virus life cycle in order to find more effective treatments against the existing drug-resistant strains as well as all the known herpesviruses.The CTC series of cobalt-containing compounds possess anti-inflammatory (105) ...

Addition of a C-Terminal Cysteine Improves the Anti-Herpes Simplex Virus Activity of a Peptide Containing the Human Immunodeficiency Virus Type 1 TAT Protein Transduction Domain

“…We therefore expected that an early event, VP-16 translocation to the nucleus, which had previously been used as a marker for viral entry, would be inhibited (10,48). When virus was adsorbed at 4°C and allowed to enter cells at 37°C, we found 48% of the nuclei were positive for VP16 (Fig.…”

“…The soluble ectodomains of the cellular receptors have also been reported to prevent entry (19,38). Although these soluble ectodomains inhibit fusion in cell culture, they have not been tested in vivo.A number of HSV entry inhibitors have been described, including a 23-amino-acid structural analog of melittin (hecate), a 33-amino-acid peptide homologous to a heptad-like repeat structure in bovine herpes virus type 1, n-docosanol, and cobalt chelates (3,4,22,40,41,43,48,53). Some of these agents may act by disrupting the membrane or envelope structure, but little is known about the actual mechanisms involved.…”

Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(III) Schiff base conjugate

“…It is well known that transition metals, such as Zn, Fe, and Co have a high affinity for histidines and cysteines. The affinity of the coordinated zinc for the histidine and cysteine residues has been used to generate transition metal inhibitors of enzymatic activity and DNA-protein interaction (21)(22)(23)(24). Displacement of the zinc ion by a Co(III) Schiff base complex [Co(III)-sb] has been shown to inhibit DNA binding of at least 1 other zinc finger transcription factor (25) and enzymatic function of non-DNA binding proteins (25)(26)(27)(28).…”

Review on supermolecules as chemical drugs

“…Its analogue CTC-96 (130) exhibited least toxicity and best activity among these series of complex supermolecules against HSV-1 and HSV-2. CTC-96 accelerated herpetic dendritic keratitis recovery better than trifluorothymidine as reference drug [235] . In addition to above complexes with antiviral activity, cobalt(Ⅲ) hexammine complex also exhibited significant antiviral activity.…”