Naphthalene carboxamides as inhibitors of human cytomegalovirus DNA polymerase

Vaillancourt, Valerie; Cudahy, Michele M.; Staley, Sandra A; Brideau, Roger J.; Conrad, Steven J.; Knechtel, Mary L.; Oien, Nancee L.; Wieber, Janet L.; Yagi, Yoshihiko; Wathen, Michael W.

doi:10.1016/s0960-894x(00)00402-9

Cited by 28 publications

(18 citation statements)

References 7 publications

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“…During an automated screen of a proprietary chemical library for specific inhibitors of the HCMV DNA polymerase a compound, PNU-26370, with modest activity against HCMV was discovered (3,22,26,32). A subsequent synthetic chemistry effort yielded a novel class of herpesvirus polymerase inhibitors, the 4-oxo-DHQs, represented by PNU-182171 and PNU-183792 (3,22,26,32).…”

Section: Resultsmentioning

confidence: 99%

“…A subsequent synthetic chemistry effort yielded a novel class of herpesvirus polymerase inhibitors, the 4-oxo-DHQs, represented by PNU-182171 and PNU-183792 (3,22,26,32). The structures of PNU-182171 and PNU-183792 are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In order to identify novel antiviral compounds that would have the potential to inhibit replication of most of the HHVs, we developed a high-throughput in vitro assay to screen for inhibitors of herpesvirus DNA polymerase activity (3,22,26,32). An automated screen of a proprietary chemical library for specific inhibitors of the HCMV DNA polymerase identified a naphthalene carboxamide, PNU-26370.…”

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confidence: 99%

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Amino Acid Changes within Conserved Region III of the Herpes Simplex Virus and Human Cytomegalovirus DNA Polymerases Confer Resistance to 4-Oxo-Dihydroquinolines, a Novel Class of Herpesvirus Antiviral Agents

Thomsen¹,

Oien²,

Hopkins³

et al. 2003

J Virol

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In vitro polymerase assays demonstrated that HSV-1, HSV-2, HCMV, VZV, and HHV-8 polymerases were inhibited by PNU-183792, whereas the HHV-6 polymerase was not. Changing this amino acid from valine to alanine in the HSV-1, HCMV, and HHV-8 polymerases alters the polymerase activity so that it is less sensitive to drug inhibition. In contrast, changing the equivalent amino acid in the HHV-6 polymerase from alanine to valine alters polymerase activity so that PNU-183792 inhibits this enzyme. The HSV-1, HSV-2, and HCMV drug-resistant mutants were not altered in their susceptibilities to nucleoside analogs; in fact, some of the mutants were hypersensitive to several of the drugs. These results support a mechanism where PNU-183792 inhibits herpesviruses by interacting with a binding determinant on the viral DNA polymerase that is less important for the binding of nucleoside analogs and deoxynucleoside triphosphates.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Amino Acid Changes within Conserved Region III of the Herpes Simplex Virus and Human Cytomegalovirus DNA Polymerases Confer Resistance to 4-Oxo-Dihydroquinolines, a Novel Class of Herpesvirus Antiviral Agents

Thomsen¹,

Oien²,

Hopkins³

et al. 2003

J Virol

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“…Highthroughput screening of small molecules in the Pharmacia compound collection using the in vitro SPA assay identified several compounds as novel nonnucleoside inhibitors of the HCMV DNA polymerase (23,24). One of the more promising leads was PNU-26370, a naphthalene carboxamide (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…One of the most promising leads from high-throughput screening for inhibitors of HCMV polymerase was a naphthalene carboxamide designated PNU-26370 (24). Structure-activity relationship (SAR) studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antivirals with unique biological properties.…”

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confidence: 99%

Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors

Oien¹,

Brideau²,

Hopkins³

et al. 2002

Antimicrob Agents Chemother

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While the treatment of herpes simplex virus type 2 (HSV-2) infections with acyclovir (ACV) and similar nucleoside analogs was one of the first success stories in antiviral chemotherapy, substantial unmet medical needs remain for diseases caused by herpesviruses. The increasing immunocompromised population, particularly AIDS patients and patients with transplants, has driven the need for improved antiviral agents to treat diseases caused by herpesviruses (6, 12). Although human cytomegalovirus (HCMV) is generally benign in the immunocompetent host, reactivation of HCMV is associated with significant morbidity and mortality in immunocompromised individuals. Active HCMV infection is associated with clinical syndromes such as pneumonia, retinitis, hepatitis, gastrointestinal disease, and congenital birth defects (2, 5, 7, 10, 12). The other human herpesviruses such as HSV-1, HSV-2, and varicella-zoster virus (VZV) also occur at a greater incidence and severity in the immunocompromised population (6, 17). Resistance to the currently available nucleoside analog antivirals does occur in this population, compounding the difficulty in treating these viral infections (11,18). Ganciclovir (GCV), foscarnet, cidofovir, and formivirsen, the only drugs approved for treatment of HCMV infections, are less than ideal agents due to their significant toxicity, modest efficacy, and poor oral bioavailability (3, 17). Clearly, less-toxic, orally available alternatives are needed for treating herpesvirus infections in immunocompromised patients. In order to address this unmet medical need, we initiated a program to identify novel nonnucleoside inhibitors of herpesvirus DNA polymerases through broad screening of our compound collection.Polymerases are classified according to their sequences and functional homologies. All herpesvirus polymerases belong to the family B DNA polymerases (1). Several eukaryotic polymerases, including human ␣ and ␦ polymerases, also belong to this family of DNA polymerases with human ␦ polymerase sharing the highest degree of homology with the herpesvirus polymerases (1). These family B DNA polymerases share six to seven highly conserved domains labeled I through VII, in decreasing order of conservation (8,9). In addition to these family B conserved domains, herpesvirus DNA polymerases share an additional conserved domain referred to as the A or ␦ domain (4). Hence, broad inhibition of herpesvirus polymerases may be possible if compounds target conserved domains shared among the herpesvirus polymerases but not shared among other eukaryotic polymerases such as human ␣ and ␦ DNA polymerases. Approximately 80,000 compounds were screened for inhibition of the HCMV polymerase. Since the goal was to identify DNA polymerase inhibitors that demonstrate broad activities against the herpesviruses with no activity against host cell DNA polymerases, active compounds were further evaluated for inhibition of the HSV-1 and VZV polymerases and human polymerases ␣, ␦, and ␥.One of the most promising leads from high-throughput

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Anti‐HCMV Compounds

Andrei¹,

Snoeck²

2011

Antiviral Drug Strategies

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Naphthalene carboxamides as inhibitors of human cytomegalovirus DNA polymerase

Cited by 28 publications

References 7 publications

Amino Acid Changes within Conserved Region III of the Herpes Simplex Virus and Human Cytomegalovirus DNA Polymerases Confer Resistance to 4-Oxo-Dihydroquinolines, a Novel Class of Herpesvirus Antiviral Agents

Amino Acid Changes within Conserved Region III of the Herpes Simplex Virus and Human Cytomegalovirus DNA Polymerases Confer Resistance to 4-Oxo-Dihydroquinolines, a Novel Class of Herpesvirus Antiviral Agents

Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors

Anti‐HCMV Compounds

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