Antiviral Activity of a Selective Ribonucleotide Reductase Inhibitor against Acyclovir-Resistant Herpes Simplex Virus Type 1 In Vivo

Duan, Jianmin; Liuzzi, Michel; Paris, William; Lambert, Michelle; Lawetz, Carol; Moss, Neil; Jaramillo, Jorge; Gauthier, Jean; Déziel, Robert; Cordingley, Michael G.

doi:10.1128/aac.42.7.1629

Cited by 36 publications

(18 citation statements)

References 44 publications

(93 reference statements)

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“…In vitro studies have shown that inhibitors of cellular RR or the HSV-1 or VZV RRs (including HU, FMdC, A723U, A1110U, BW348U87, and the “BILD” series of peptidomimetics) exhibit antiviral activity when used alone and either potentiate or result in synergy when used in combination with ACV against wild type or drug-resistant strains of VZV, HSV-1, or HSV-2 (Bridges et al, 1995; Duan et al, 1998; Ellis et al, 1989; Lawetz and Liuzzi, 1998; Liuzzi et al, 1994; Moss et al, 1996, 1995; Neyts and De Clercq, 1999; Prichard and Shipman, 1995; Sergerie and Boivin, 2008; Spector et al, 1985, 1987, 1989). HU has also been shown to potentiate the activity of cidofovir and to synergize with GCV to inhibit replication of wild type or drug-resistant strains of HSV-1 or HSV-2 (Neyts and De Clercq, 1999; Sergerie and Boivin, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In murine models of HSV-1- or HSV-2-induced cutaneous or ocular lesions, RR inhibitors administered topically showed therapeutic efficacy and exhibited potentiation or synergy when used in combination with ACV (Brandt et al, 1996; Bridges et al, 1995; Duan et al, 1998; Ellis et al, 1989; Liuzzi et al, 1994; Lobe et al, 1991; Moss et al, 1995, 1996; Spector et al, 1992). Combination therapies were also effective for treating lesions caused by ACV-resistant strains (Duan et al, 1998; Ellis et al, 1989; Lobe et al, 1991; Spector et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

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Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir

2013

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Ganciclovir (GCV) is a deoxyguanosine analog that is effective in inhibiting human cytomegalovirus (HCMV) replication. In infected cells GCV is converted to GCV-triphosphate which competes with dGTP for incorporation into the growing DNA strand by the viral DNA polymerase. Incorporated GCV promotes chain termination as it is an inefficient substrate for elongation. Because viral DNA synthesis also relies on cellular ribonucleotide reductase (RR) to synthesize deoxynucleotides, RR inhibitors are predicted to inhibit HCMV replication. Moreover, as dGTP competes with GCV-triphosphate for incorporation, RR inhibitors may also synergize with GCV by reducing intracellular dGTP levels and there by promoting increased GCV-triphosphate utilization by DNA polymerase. To investigate potential of RR inhibitors as anti-HCMV agents both alone and in combination with GCV, HCMV-inhibitory activities of three RR inhibitors, hydroxyurea, didox, and trimidox, were determined. In both spread inhibition and yield reduction assays RR inhibitors had modest anti-HCMV activity with 50% inhibitory concentrations ranging from 36 ± 1.7 to 221 ± 52 µM. However, all three showed significant synergy with GCV at concentrations below their 50% inhibitory and 50% toxic concentrations. These results suggest that combining GCV with relatively low doses of RR inhibitors could significantly potentiate the anti-HCMV activity of GCV in vivo and could improve clinical response to therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir

2013

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“…The peptidomimetic drugs prevent the formation of an active RR by competitively inhibiting the binding of R2 to R1 [313][314][315][316][317]. The difference between the C terminus sequence of R2 of different species is important to develop highly specific inhibitors that can inhibit a parasite RR without interfering with the host RR [313,314,318,319]. A herpes simplex virus (HSV) RR inhibitor, BILD 1633 SE has shown activity against cutaneous acyclovir-resistant HSV-1 infections in an athymic nude mouse model.…”

Section: Polymerization Inhibitionmentioning

confidence: 99%

Ribonucleotide Reductase Inhibitors and Future Drug Design

Shao¹,

Zhou²,

Chu³

et al. 2006

CCDT

247

249

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Ribonucleotide reductase (RR) is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for DNA replication and repair. The key role of RR in DNA synthesis and cell growth control has made it an important target for anticancer therapy. Increased RR activity has been associated with malignant transformation and tumor cell growth. Efforts for new RR inhibitors have been made in basic and translational research. In recent years, several RR inhibitors, including Triapine, Gemcitabine, and GTI-2040, have entered clinical trial or application. Furthermore, the discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment. This review compiles recent studies on (1) the structure, function, and regulation of two forms of RR; (2) the role in tumorigenesis of RR and the effect of RR inhibition in cancer treatment; (3) the classification, mechanisms of action, antitumor activity, and clinical trial and application of new RR inhibitors that have been used in clinical cancer chemotherapy or are being evaluated in clinical trials; (4) novel approaches for future RR inhibitor discovery.

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“…These inhibitors are based on the C-terminal amino acid sequence of the HSV RR small subunit (R2), VVNDL, which bind to the RR large subunit (R1) and permits subunit association and subsequent catalytic activity. The inhibitors, which mimic this C-terminal sequence, but are modified to enhance stability, competing with R2 for binding to R1, show antiviral activity in vivo, suppress the replication of HSV-1, HSV-2 and acyclovir-resistant HSV strains in cell culture, and also strongly potentiate the antiviral activity of acyclovir [56][57][58][59].…”

Section: Peptides As Inhibitors Of Protein-protein Interactionsmentioning

confidence: 98%

Interfering with Protein-Protein Contact: Molecular Interaction Maps and Peptide Modulators

Nieddu

Pasa²

2007

CTMC

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Protein-protein interactions (PPIs) can be useful targets for different pathologies. In fact controlling a function or attempting to repair an anomaly often means interfering with the cross-talk among different proteins. In order to have a general view of these cross-talks, Molecular Interaction Maps (MIMs) are used, organizing the enormous available information that is added every day and trying to understand the most suitable and accurate targets for any specific cell alteration. In this paper the c-Myc protein is taken as an example to explain the use of a map. The discovery of a peptidomimetic antagonist of c-Myc, active against proliferation of cancer cell lines, is reported and a possible mechanism of action is explained. To interfere with a specific protein-protein contact, a good starting point can be to consider a protein entity. Because the interaction between two proteins is normally characterized by a wide zone of contact, relative large inhibitors could be more convenient in the first approaches. Therefore, peptides mimicking the interacting zone can be considered as potential leads in the rational design of effective molecules. Here different examples of peptides as protein-protein interaction inhibitors are reported.

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Antiviral Activity of a Selective Ribonucleotide Reductase Inhibitor against Acyclovir-Resistant Herpes Simplex Virus Type 1 In Vivo

Cited by 36 publications

References 44 publications

Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir

Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir

Ribonucleotide Reductase Inhibitors and Future Drug Design

Interfering with Protein-Protein Contact: Molecular Interaction Maps and Peptide Modulators

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