Mode of action of a new type of UDP-glucose analog against herpesvirus replication

Alarcón, Balbino; González, María Eugenia Pérez; Carrasco, Luís; Méndez-Castrillón, Paloma P.; García-López, M. Teresa; Heras, F. G. De Las

doi:10.1128/aac.32.8.1257

Cited by 7 publications

(6 citation statements)

References 15 publications

(22 reference statements)

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“…One hour later, the medium was removed, and the proteins were collected for electrophoresis in 15% polyacrylamide gels as previously described (1,5). To obtain specific * Corresponding author.…”

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confidence: 99%

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6-(3,4-Dichlorophenoxy)-3-(ethylthio)-2-pyridincarbonitrile inhibits poliovirus uncoating

González

Almela

Yacout

et al. 1990

Antimicrob Agents Chemother

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We investigated the mode of action of 6-(3,4-dichlorophenoxy-3-(ethylthio)-2-pyridincarbonitrile against poliovirus. This agent effectively blocked the synthesis of poliovirus proteins and RNA when it was added at the beginning of infection. Poliovirus attachment and internalization into HeLa cells were not inhibited in the presence of the compound; poliovirus uncoating was the target of its activity. Antiviral agents are of significant interest for at least two main reasons: (i) to provide a remedy for virus-caused diseases and (ii) as tools to get insights into the molecular mechanisms by which animal viruses replicate (3,4,9). A search for new antipicornavirus agents led to the discovery of 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile as a broadspectrum antiviral agent (17). Initial studies on its mode of action indicated that this compound acted at an early step, after uncoating, that is required for viral RNA synthesis (19). Based on these findings, several phenoxybenzenes and phenoxypyridines were analyzed by Kenny et al. (11). 6-(3,4-Dichlorophenoxy)-3-(ethylthio)-2-pyridincarbonitrile (DEPC) showed the best antipicornavirus activity (11). It was particularly effective against several rhinoviruses, coxsackievirus A21, echovirus 12, and poliovirus 2. Since this compound was inactive against coxsackievirus when added 3 h after infection, it was suggested that DEPC blocked an early step of virus growth. Indeed, the uncoating of photosensitized coxsackievirus A21 was reduced when 2 ,Lg of this compound per ml was present (11). However, this test does not discriminate between the binding of virus particles to cells, its internalization, and viral uncoating. As yet, no studies are available on the potential inhibition of virus attachment by these agents.Poliovirus type 1 (Mahoney strain) was grown in HeLa cells. The procedures for cell culture and the plaque assay for virus titration were as described previously (8). The compound DEPC was kindly given by Merrell-Dow Pharmaceuticals (Indianapolis, Ind.). The full-length poliovirus genome probe was obtained by EcoRI restriction enzyme digestion of the pSVO poliovirus vector. The restriction fragment was recovered from low-melting-point agarose gels by electrophoresis and was labeled with [a-32P]dATP (400 Ci/mmol; The Radiochemical Centre, Amersham, England) by nick translation. HeLa cells were infected with poliovirus at -1 h in Dulbecco modified Eagle medium supplemented with 2% heat-inactivated newborn calf serum. One hour later (0 h), unattached virus was removed, the cell monolayer was washed twice, and fresh medium was added.To assay for protein synthesis cells were incubated in methionine-free medium in the presence of 5 ,uCi of[35S]methionine (1,100 Ci/mmol; The Radiochemical Centre) per ml. One hour later, the medium was removed, and the proteins were collected for electrophoresis in 15% polyacrylamide gels as previously described (1, 5). To obtain specific * Corresponding author. incorporation of [3H]uridine into viral RNA, 5 pug of actinomycin D (Sigma C...

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“…To assay for protein synthesis cells were incubated in methionine-free medium in the presence of 5 ,uCi of [35S]methionine (1,100 Ci/mmol; The Radiochemical Centre) per ml. One hour later, the medium was removed, and the proteins were collected for electrophoresis in 15% polyacrylamide gels as previously described (1,5).…”

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confidence: 99%

6-(3,4-Dichlorophenoxy)-3-(ethylthio)-2-pyridincarbonitrile inhibits poliovirus uncoating

González

Almela

Yacout

et al. 1990

Antimicrob Agents Chemother

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“…[1] Furthermore, studies of structurally related compounds within this series showed that the nucleotide-like 5'-Osulfamoyluridine moiety is an important component for the maintenance of antiviral activity, and it was suggested that this moiety and/or its metabolites could be responsible for the observed inhibition of DNA synthesis and protein glycosylation. [2] More recently, lipophilic nucleotide mimics in which 2',3'-dideoxynucleoside (ddN) residues were linked to a glucopyranosyl moiety by the OSO 2 NHCOO group were shown to exhibit anti-HIV-1 activity in MT-4 cells at concentrations well below the toxicity threshold. [3] In this case, it was suggested that these compounds do not release the free ddNs, which are known to be potent and selective inhibitors of HIV replication (by inhibiting HIV reverse transcriptase), but may act in their own right.…”

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confidence: 99%

A General Buffer-Acid-Catalyzed C−O Cleavage Reaction in the Hydrolysis of PhenylN-(Phenoxycarbonyl)sulfamate Ester

Blans

Vigroux

1999

Chem. Eur. J.

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Rate constants and products are reported for the aqueous decomposition (pH 0 ± 14) of phenyl N-(phenoxycarbonyl)sulfamate (pK a 1.18) at 50 8C. The pH ± rate profile indicates a rate law that includes three terms: two pH-independent terms, k a in acid and k p around neutral pH, with k a b k p , and a hydroxide-ion-dependent term, k OH . The observation of non-first-order behavior in the pH range between 1.6 and 4.1 points to the accumulation of a nonsteady-state intermediate that is concluded to be phenyl sulfamate. The latter result, coupled with the observation at low pH of general acid catalysis by buffers, reveals that each of the hydrolytic paths involves i) the anionic form specifically and ii) carbon ± oxygen bond fission. Buffer catalysis is assumed to be the result of the nonexistence of the zwitterionic species PhOSO 2 N À CO ± O (H)Ph. Comparison with previously studied phenyl N-(phenylsulfonyl)carbamate [7] indicates that the Brùnsted a value associated with such a mechanism increases sharply as the CÀO bond which is cleaved becomes stronger (a change in reactivity of ca. 2.3 kcal mol À1gives rise to a change in a of about 0.3). In contrast to CÀO cleavage, SÀO and PÀO fissions involved in related systems such as N-(methoxycarbonyl)sulfamate esters and phosphate and sulfate monoesters with good leaving groups do not exhibit buffer-acid catalysis. It is concluded that unambiguous distinction between inter-and intramolecular general acid catalysis is not currently possible for those compounds.

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“…The genetic materials DNA and RNA are phosphodiesters, and most of the coenzymes are esters of phosphoric or pyrophosphoric acid. Recently, a new type of analogue of uridine 5‘-diphosphate glucose (UDP-Glc), in which the naturally occurring diphosphate group has been replaced by an isosteric O−SO 2 NHCO−O group, were found to interfere with protein glycosylation, inhibiting the glycosylation of viral proteins to a greater extent than glycosylation of cellular proteins . Although these analogues were initially designed to interfere with the glycosylation process and, do in fact, inhibit it, their mode of action proved to be more complex since they also inhibit DNA synthesis 1b.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a new type of analogue of uridine 5‘-diphosphate glucose (UDP-Glc), in which the naturally occurring diphosphate group has been replaced by an isosteric O−SO 2 NHCO−O group, were found to interfere with protein glycosylation, inhibiting the glycosylation of viral proteins to a greater extent than glycosylation of cellular proteins . Although these analogues were initially designed to interfere with the glycosylation process and, do in fact, inhibit it, their mode of action proved to be more complex since they also inhibit DNA synthesis 1b. In recent therapeutic strategies, the extended use of the −SO 2 NHCO− groupas a replacement for the diphosphate or sulfate moiety of a variety of critical biomoleculesproved to be successful as well. − Also, the ionized form of this spacer was used to design an unusual water-soluble ACAT inhibitor which is well absorbed and thus exhibits improved bioavailability …”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Decomposition of Aryl N-(Methoxycarbonyl)sulfamates in Aqueous Media

Blans

Vigroux

1998

J. Am. Chem. Soc.

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Rate constants and products are reported for the decomposition of aryl N-(methoxycarbonyl)sulfamates 1a − h (range) in aqueous solutions (pH 0−14) at 50 °C. The pK a values at 25 °C of 1a − h are 0.46−2.40. The pH-rate profiles of 1 indicate a rate law that includes three terms: two pH independent terms, k a in acid and k p around neutral pH, with k a > k p, and a hydroxide ion dependent term, k OH. In acid, product analysis reveals that both S−O (k SO2) and C−O (k CO) bond cleavage reactions are involved. From an analysis of βlg, solvent isotope effects, and solvent isotopic labeling of the products, it is concluded (a) that the C−O cleavage reaction involves protonation of the leaving group methanol and its expulsion from the dipolar intermediate ArOSO2N-CO−O+HCH3 and (b) that the S−O cleavage reaction may involve either an intra- or an intermolecular general acid-catalyzed decomposition of 1 or 1 - , respectively. In contrast to k a, the spontaneous hydrolysis reaction of 1 - , k p, takes place exclusively via S−O bond fission. The k OH reaction of 1 - is rationalized by OH- attack either at the carbonyl center (1b − h) or at the aromatic ring (1a). It is concluded that the −SO2NHCO− group may be viewed as an attractive phosphate analogue.

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Mode of action of a new type of UDP-glucose analog against herpesvirus replication

Cited by 7 publications

References 15 publications

6-(3,4-Dichlorophenoxy)-3-(ethylthio)-2-pyridincarbonitrile inhibits poliovirus uncoating

6-(3,4-Dichlorophenoxy)-3-(ethylthio)-2-pyridincarbonitrile inhibits poliovirus uncoating

A General Buffer-Acid-Catalyzed C−O Cleavage Reaction in the Hydrolysis of PhenylN-(Phenoxycarbonyl)sulfamate Ester

Mechanisms of Decomposition of Aryl N-(Methoxycarbonyl)sulfamates in Aqueous Media

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