Specific Recognition of the Bicyclic Pyrimidine Nucleoside Analogs, a New Class of Highly Potent and Selective Inhibitors of Varicella-Zoster Virus (VZV), by the VZV-Encoded Thymidine Kinase

Sienaert, Rebecca; Naesens, Lieve; Brancale, Andrea; Clercq, Erik De; McGuigan, Christopher; Balzarini, Jan

doi:10.1124/mol.61.2.249

Cited by 48 publications

(37 citation statements)

References 24 publications

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“…Interestingly, although both ACV and PCV are activated by the viral TK, they select for drug-resistant virus strains that exhibit a different genotype (i.e., mutations in TK and DNA polymerase, respectively) (G. (Table 4) whereas ACV-resistantvirus is cross-resistant to all TK-dependent drugs (Table 2). When all virus resistance data are taken together, they confirm that the VZVencoded TK is essential for the phosphorylation of the BCNAs and for their eventual anti-VZV activity (16). Indeed, the BCNAs used in this study have also been evaluated for their affinity for purified VZV and herpes simplex virus type 1 (HSV-1) TK (4).…”

Section: Discussionmentioning

confidence: 86%

Susceptibilities of Several Clinical Varicella-Zoster Virus (VZV) Isolates and Drug-Resistant VZV Strains to Bicyclic Furano Pyrimidine Nucleosides

Andrei

Sienaert

McGuigan

et al. 2005

Antimicrob Agents Chemother

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Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency inVaricella-zoster virus (VZV) is an alphaherpesvirus that is known to be responsible for varicella in young children and for localized recurrent lesions (called zoster) later in life, due to reactivation in the ganglia. The disease can be severe in immunocompromised patients such as AIDS patients or transplant recipients. The reference drug for the treatment of immunocompromised patients presenting with VZV infections and of patients presenting with zoster is acyclovir (ACV) (7). Recently, brivudine (BVDU), another nucleoside analog, has been marketed for the treatment of varicella and zoster (15,23).We have demonstrated that several members of a new class of antivirals, the bicyclic pyrimidine nucleoside analogues (BCNAs), are highly potent and selective inhibitors of VZV in vitro (3-5, 12, 13, 16-18). This new class of compounds exhibits exclusive specificity for VZV and obligatorily requires an alkyl or alkylaryl side chain at the furan moiety for potent anti-VZV activity.ACV-resistant VZV strains have been reported to emerge with increasing frequency in immunocompromised patients after long-term therapy with ACV (1). These observations justify drug sensitivity evaluation of resistant viral strains obtained after exposure to molecules belonging to different classes of antiviral agents.The present work demonstrates the exquisite antiviral activity of a selection of the most potent BCNAs against a broad range of clinical VZV isolates. These BCNA molecules were also investigated for their activity against VZV strains that were selected in the presence of several of the BCNAs, demonstrating that the BCNAs select for drug-resistant VZV phenotypes resulting from mutations in the virus-encoded thymidine kinase (TK).

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Section: Discussionmentioning

confidence: 86%

Susceptibilities of Several Clinical Varicella-Zoster Virus (VZV) Isolates and Drug-Resistant VZV Strains to Bicyclic Furano Pyrimidine Nucleosides

Andrei

Sienaert

McGuigan

et al. 2005

Antimicrob Agents Chemother

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“…Substrate activity for VZV TK has indeed been demonstrated for several bicyclic nucleoside analogues, including lead compounds 1a and 2e (Sienaert et al, 2002;. Further evaluation of compounds 6a-6g (data not shown) showed a complete absence of antiviral activity in cell culture against human CMV, HSV-1 and HSV-2, and VV, indicating that the compounds are VZV-specific in their action.…”

Section: Discussionmentioning

confidence: 99%

Bicyclic Nucleoside Inhibitors of Varicella-Zoster Virus: Effect of Terminal Aryl Substitution in the Side-Chain

Carangio

Srinivasan

McGuigan

et al. 2002

Antivir Chem Chemother

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We have previously reported novel, highly potent and selective nucleoside inhibitors of varicella-zoster virus (VZV) bearing unusual fluorescent bicyclic base moieties (McGuigan et al., 1999). These bicyclic furanopyrimidine nucleosides displayed potencies against various strains of VZV in cell culture that were approximately 300-fold higher than those of current anti-VZV agents, such as acyclovir. Our initial studies identified the absolute requirement of a long alkyl side-chain, with an optimal chain length of C8-C10, for antiviral activity (McGuigan et al., 1999) as typified by structures 1a-1c (Figure 1). The key consequence of the obligate long alkyl side-chain is the inherent lipophilicity of the bicyclic systems and we noted that the most active nucleosides had calculated octanol-water logP [ClogP] values in the range of 2.4-3.5 (ClogP version 1.0, Biobyte Corporation, Claremont, CA). With a view to further exploring the structure-activity relationships (SARs) of this class of compounds, we carried out several types of structural modification in the alkyl side-chain. In the first instance, we examined the effect of halogen substitution at the terminus of a nonyl side-chain and found that this was well tolerated; and notably with ClogP values of the ω-halo compounds falling roughly within the previously noted optimal range. We therefore, proposed a possible correlation between antiviral activity and overall compound lipophilicity and also reported on the negative impact on antiviral activity of enhancing the aqueous solubility of the bicyclic nucleosides (Brancale et al., 2000b), this being attributed to the consequential impact on logP. More recently, we sought to constrain the highly flexible alkyl side-chains into more restricted conformations by the use of ring moieties, whilst retaining overall compound lipophilicity. Following the introduction of a phenyl group at the 6-position of the bicyclic base, between the furo ring and the alkyl side-chain, we observed an astonishing enhancement of both potency and selectivity against VZV . The new lead p-alkylphenyl bicyclic nucleosides, as typified by structures 2a-2g (Figure 1), displayed potencies that were, by comparison, approximately 50-fold higher than those for alkyl analogues of identical ClogP. In keeping with our proposed correlation,

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“…For example, BVDU (De Clercq, 2004) has more than 10 3 -fold superiority in potency over acyclovir (Roberts et al, 1991;Ashida et al, 1997;Kussmann-Gerber et al, 1998;Sienaert et al, 2002). In the case of the Y21E thymidine kinase mutant, the IC 50 value for this class of inhibitors seems to be very similar to the wild type, whereas for Y21H thymidine kinase, the IC 50 value was increased approximately 10-fold.…”

Section: Resultsmentioning

confidence: 98%

Mutations Distal to the Substrate Site Can Affect Varicella Zoster Virus Thymidine Kinase Activity: Implications for Drug Design

Omari¹,

Liekens²,

Bird³

et al. 2006

Mol Pharmacol

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Varicella zoster virus encodes a thymidine kinase responsible for the activation of antiherpetic nucleoside prodrugs such as acyclovir. In addition, herpes virus thymidine kinases are being explored in gene/chemotherapy strategies aimed at developing novel antitumor therapies. To investigate and improve compound selectivity, we report here structure-based site-directed mutagenesis studies of varicella zoster virus thymidine kinase (VZVTK). Earlier reports showed that mutating residues at the core of the VZVTK active site invariably destroyed activity; hence, we targeted more distal residues. Based on the VZVTK crystal structure, we constructed six mutants (E59S, R84V, H97Y/A, and Y21H/E) and tested substrate activity and competitive inhibition for several compound series. All VZVTK mutants tested retained significant phosphorylation activity with dThd as substrate, apart from Y21E (350-fold diminution in the k cat /K m ). Some mutations give slightly improved affinities: bicyclic nucleoside analogs (BCNAs) with a p-alkyl-substituted phenyl group seem to require aromatic ring stacking interactions with residue 97 for optimal inhibitory effect. Mutation Y21E decreased the IC 50 value for the BCNA 3-(2Ј-deoxy-␤-(Cf1368) 4-fold, whereas mutation Y21H increased the IC 50 value by more than 15-fold. These results suggest that residue 21 is important for BCNA selectivity and might explain why HSV1TK is unable to bind BCNAs. Other mutants, such as the E59S and R84V thymidine kinases, which in wild-type VZVTK stabilize the dimer interface, give opposite results regarding the level of sensitivity to BCNAs. The work described here shows that distal mutations that affect the VZVTK active-site may help in the design of more selective substrates for gene suicide therapy or as anti-varicella zoster virus drugs.

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Specific Recognition of the Bicyclic Pyrimidine Nucleoside Analogs, a New Class of Highly Potent and Selective Inhibitors of Varicella-Zoster Virus (VZV), by the VZV-Encoded Thymidine Kinase

Cited by 48 publications

References 24 publications

Susceptibilities of Several Clinical Varicella-Zoster Virus (VZV) Isolates and Drug-Resistant VZV Strains to Bicyclic Furano Pyrimidine Nucleosides

Susceptibilities of Several Clinical Varicella-Zoster Virus (VZV) Isolates and Drug-Resistant VZV Strains to Bicyclic Furano Pyrimidine Nucleosides

Bicyclic Nucleoside Inhibitors of Varicella-Zoster Virus: Effect of Terminal Aryl Substitution in the Side-Chain

Mutations Distal to the Substrate Site Can Affect Varicella Zoster Virus Thymidine Kinase Activity: Implications for Drug Design

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