Inhibition of HCMV DNA processing by a new class of anti-HCMV compounds (benzimidazole ribosides) is mediated through the UL89 gene product

Underwood, Mark; Stanat, Sylvia C.; Townsend, L B; Drach, John C.; Biron, Karen K.

doi:10.1016/0166-3542(95)94830-u

Cited by 79 publications

(166 citation statements)

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“…Of particular note is the difference at position 1107 of exon 2 resulting in a change from an aspartic acid in AD169 to a glutamic acid in Towne at amino acid 666. A similar change of aspartic acid to glutamic acid at amino acid 344 results in 10-fold resistance to the benzimidazole ribonucleosides (Underwood et al, 1998). The differences in benzimidazole sensitivity also could be related to the difference at position 145 of exon 2, which resulted in a serine to alanine change at amino acid 345.…”

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confidence: 93%

“…In studies with AD169, 10-fold resistance resulted from single mutations in the UL89 open reading frame (ORF) (Asp344Glu or Ala355Thr), and 30-fold resistance resulted from a combination of both the position 344 and 355 mutations in UL89 (Underwood et al, 1998). In studies with Towne, a resistant mutant was identified (isolate C4) that was ~30-fold resistant to the benzimidazole ribonucleosides.…”

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confidence: 99%

“…The benzimidazole ribonucleosides have a unique mode of action in that there is no effect on the synthesis of viral DNA (Underwood et al, 1998). Instead, these compounds inhibit the cleavage of high molecular weight, concatemeric viral DNA to monomeric genome-length units (Underwood et al, 1998).…”

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confidence: 99%

“…The least changes were found in UL51; the most dramatic differences were in the UL77 ORF, where Towne strain encoded a protein that was seven amino acids shorter than the protein encoded by AD169. It is most likely that the differences between strains AD169 and Towne that resulted in altered sensitivity to the benzimidazole ribonucleosides are located in either the UL89 or the UL56 ORFs because the products of both of these genes have been linked to the activity of these compounds (Krosky et al, 1998;Underwood et al, 1998). All of the coding changes in the UL56 ORF resulted in the conservative substitution of an alanine in Towne for a valine in AD169, and thus are less likely to be the cause of the difference in drug sensitivity.…”

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confidence: 99%

“…The differences in benzimidazole sensitivity also could be related to the difference at position 145 of exon 2, which resulted in a serine to alanine change at amino acid 345. This is next to the mutation site at amino acid 344, which renders benzimidazole resistance (Underwood et al, 1998).…”

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Differences in DNA Packaging Genes and Sensitivity to Benzimidazole Ribonucleosides between Human Cytomegalovirus Strains AD169 and Towne

Krosky

Ptak

Underwood

et al. 2000

Antivir Chem Chemother

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The AD169 strain of human cytomegalovirus was approximately twofold more sensitive to poly-halogenated benzimidazole ribonucleosides than Towne strain. Sequence differences between the two strains have been identified in genes UL51, UL52, UL56, UL77, UL89 and UL104. Because these genes are involved in cleavage and packaging of viral DNA and the benzimidazole ribonucleosides inhibit this process, these sequence differences may be involved in the difference in drug sensitivity.

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confidence: 93%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Differences in DNA Packaging Genes and Sensitivity to Benzimidazole Ribonucleosides between Human Cytomegalovirus Strains AD169 and Towne

Krosky

Ptak

Underwood

et al. 2000

Antivir Chem Chemother

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Synthesis of Imidazo[4,5‐b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides

Zhu

Saluja

Drach

et al. 1998

J Chinese Chemical Soc

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Wehave recently found that 2,5,6-trichloro-H~-D-ribofuranosyl)benzimidazole(TCRB) and the corresponding 2-bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet, These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,S-b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole uucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2-substituted 6,7-dichloroimidazo[4,5-b]quinoxaiines involving a reaction of 2,3,6,7tetrachloroquinoxaliue with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7-dichloroimidazo[4,5-b]quinoxatin-2-one. Ribosylation of 2-substituted imidazo [4,5b]quinoxaiines was influenced by the functional group at the 2-position and the 2-one compound was found to smoothly undergo ribosylation. The 2-one group of the nucleoside was converted into specifically selected 2-substituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, thai the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.

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Recent strategies in the development of new human cytomegalovirus inhibitors

Martı́nez¹,

Castro²,

Gil³

et al. 2001

Medicinal Research Reviews

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Human cytomegalovirus (HCMV) is one of the most common opportunistic infections in immunucompromised individuals, such as AIDS patients and organ transplant recipients, and is the most frequent congenital viral infection in humans. Despite a reduction of the incidence of AIDS‐related opportunistic infections in patients under highly active antiretroviral treatment, attention should be paid to the HCMV risk factor in these individuals. Furthermore, HCMV may have an important role in atherosclerosis. Existing antiviral treatments for the HCMV infection suffer from poor bioavailability, toxicity, and limited effectiveness, mainly due to the development of drug resistance. Fortunately there are novel and potentially very effective new compounds undergoing pre‐clinical and clinical evaluation. This review provides an overview in the last five years of new HCMV inhibitors (chemical structures, SAR, and new mechanisms of action) with the aim to provide new clues for the development of future drugs against this opportunistic virus. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 227–244, 2001

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Inhibition of HCMV DNA processing by a new class of anti-HCMV compounds (benzimidazole ribosides) is mediated through the UL89 gene product

Cited by 79 publications

References 0 publications

Differences in DNA Packaging Genes and Sensitivity to Benzimidazole Ribonucleosides between Human Cytomegalovirus Strains AD169 and Towne

Differences in DNA Packaging Genes and Sensitivity to Benzimidazole Ribonucleosides between Human Cytomegalovirus Strains AD169 and Towne

Synthesis of Imidazo[4,5‐b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides

Recent strategies in the development of new human cytomegalovirus inhibitors

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