A Solid-Phase Assay for the Binding of Peptidic Subunit Association Inhibitors to the Herpes Simplex Virus Ribonucleotide Reductase Large Subunit

Krogsrud, Richard L.; Welchner, Ewald; Scouten, Erika; Liuzzi, Michel

doi:10.1006/abio.1993.1436

Cited by 24 publications

(21 citation statements)

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“…Figure 1 shows the structure of the HSV RR subunit association inhibitor BILD 1633 SE. This compound inhibits HSV RR with a 50% inhibitory concentration of 3 nM, as determined by a competitive binding assay (24). Like previously published inhibitors in this class, it does not affect the activity of the human RR at a concentration up to 250 M, on the basis of the enzyme assay.…”

Section: Comparative In Vitro Activities Of Bild 1633 Se and Acvsupporting

confidence: 50%

“…Although ACV has generally been successful in treating HSV infections, chronic therapy with this drug in patients who are immunocompromised due to AIDS, organ transplantation, or cancer chemotherapy leads to an increase in the viral burden and the possible emergence of resistance. It has recently been reported that ACV-resistant mutants are responsible for HSV pneumonia, progressive whitlow, meningoencephalitis, and mucocutaneous dissemination in AIDS patients (7,8,(22)(23)(24)34). The unfulfilled clinical needs call for continued investigation to identify novel therapeutic antiherpesvirus agents.…”

Section: Discussionmentioning

confidence: 99%

“…Herpes simplex virus (HSV) encodes a ribonucleotide reductase (RR) that catalyzes the synthesis of the deoxyribonucleotide precursors required for DNA synthesis. This enzyme shares many similarities with the host cellular RR but differs markedly from the latter in terms of primary amino acid sequences and allosteric regulation (24,26,35). Both RRs consist of two subunits (26,35).…”

mentioning

confidence: 99%

“…Both RRs consist of two subunits (26,35). The larger subunit contains redox-active thiols that provide the hydrogen for nucleotide reduction (24,29,31,35). The smaller subunit contains a binuclear -oxo bridged iron center associated with a tyrosyl free radical (1,17,26,32,35).…”

mentioning

confidence: 99%

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

Duan

Liuzzi

Paris

et al. 1998

Antimicrob Agents Chemother

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The present study reports the activity of BILD 1633 SE against acyclovir (ACV)-resistant herpes simplex virus (HSV) infections in athymic nude (nu/nu) mice. BILD 1633 SE is a novel peptidomimetic inhibitor of HSV ribonucleotide reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mutants. Its in vivo activity was tested against cutaneous viral infections in athymic nude mice infected with the ACV-resistant isolates HSV type 1 (HSV-1) dlsptk and PAAr5, which contain mutations in the viral thymidine kinase gene and the polymerase gene, respectively. Following cutaneous infection of athymic nude mice, both HSV-1 dlsptk and PAAr5 induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. A 10-day treatment regimen with ACV given topically four times a day as a 5% cream or orally at up to 5 mg/ml in drinking water was partially effective against HSV-1 PAAr5 infection with a reduction of the area under the concentration-time curve (AUC) of 34 to 48%. The effects of ACV against HSV-1 dlsptk infection were not significant when it was administered topically and were only marginal when it was given in drinking water. Treatment under identical conditions with 5% topical BILD 1633 SE significantly reduced the cutaneous lesions caused by both HSV-1 dlsptk and PAAr5 infections. The effect of BILD 1633 SE against HSV-1 PAAr5 infections was more prominent and was inoculum and dose dependent, with AUC reductions of 96 and 67% against infections with 106 and 107 PFU per inoculation site, respectively. BILD 1633 SE also significantly decreased the lesions caused by HSV-1dlsptk infection (28 to 51% AUC reduction). Combination therapy with topical BILD 1633 SE (5%) and ACV in drinking water (5 mg/ml) produced an antiviral effect against HSV-1 dlsptk and PAAr5 infections that was more than the sum of the effects of both drugs. This is the first report that a selective HSV RR subunit association inhibitor can be effective against ACV-resistant HSV infections in vivo.

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Section: Comparative In Vitro Activities Of Bild 1633 Se and Acvsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Duan

Liuzzi

Paris

et al. 1998

Antimicrob Agents Chemother

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“…Strong interest in this enzyme as a therapeutic target arose from the discovery that a nonapeptide corresponding to the HSV R2 C-terminus specifically inhibits enzyme activity by impairing subunit interaction [20][21][22]. Even though empirical modifications of this nonapeptide have led to the synthesis of shorter compounds exhibiting very high inhibitory potency in itro [23][24][25] and antiviral activity in i o [26], the knowledge of the tertiary structure of the HSV holoenzyme would facilitate the design of smaller inhibitory compounds able to reach their R1 intracellular target more efficiently. As a first step towards this goal, E. coli expression vectors and purification methods were developed for HSV-1 R1 and R2 [9,10,17,27].…”

Section: Introductionmentioning

confidence: 99%

Production of the R2 subunit of ribonucleotide reductase from herpes simplex virus with prokaryotic and eukaryotic expression systems: higher activity of R2 produced by eukaryotic cells related to higher iron-binding capacity

Lamarche

Matton

Massie³

et al. 1996

Biochemical Journal

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The R2 subunit of ribonucleotide reductase from herpes simplex virus type 2 was overproduced with prokaryotic and eukaryotic expression systems. The recombinant R2 purified by a two-step procedure exhibited a 3-fold higher activity when produced in eukaryotic cells. Precise quantification of the R2 concentration at each step of the purification indicated that the activity was not altered during the purification procedure. Moreover, we have observed that the level of R2 expression, in eukaryotic cells as well as in prokaryotic cells, did not influence R2 activity. Extensive characterization of the recombinant R2 purified from eukaryotic and prokaryotic expression systems has shown that both types of pure R2 preparations were similar in their 76 kDa dimer contents (more than 95%) and in their ability to bind the R1 subunit. However, we have found that the higher activity of R2 produced in eukaryotic cells is more probably related to a higher capability of binding the iron cofactor as well as a 3-fold greater ability to generate the tyrosyl free radical.

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Peptide Drug Discovery and Development

2011

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A Solid-Phase Assay for the Binding of Peptidic Subunit Association Inhibitors to the Herpes Simplex Virus Ribonucleotide Reductase Large Subunit

Cited by 24 publications

References 0 publications

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

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

Production of the R2 subunit of ribonucleotide reductase from herpes simplex virus with prokaryotic and eukaryotic expression systems: higher activity of R2 produced by eukaryotic cells related to higher iron-binding capacity

Peptide Drug Discovery and Development

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