9-Arylpurines as a Novel Class of Enterovirus Inhibitors

Aguado, Leire; Thibaut, Hendrik Jan; Priego, Eva-Marı́a; Jimeno, M. Luísa; Camarasa, Marı́a-José; Neyts, Johan; Pérez‐Pérez, María‐Jesús

doi:10.1021/jm901240p

Cited by 29 publications

(28 citation statements)

References 41 publications

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“…We recently described a series of 9-arylpurines that inhibit in vitro enterovirus replication [29]. From this series, we selected TP219 (designated compound 26 in reference [29]) for further mechanistic studies (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

et al. 2014

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Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis.

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Section: Resultsmentioning

confidence: 99%

“…From this series, we selected TP219 (designated compound 26 in reference [29]) for further mechanistic studies (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

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Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

et al. 2014

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“…Similar reactions are well known in syntheses of thiazolopyrimidine derivatives [10][11][12][13]. It should be noted that on carrying out this reaction it is also possible to expect the formation of tricyclic structures 4a-c with a purine fragment (see analogies in [14][15][16][17][18]). However in all cases only the formation of compounds 3a-c in fairly high yields were observed (65-71%).…”

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Synthesis and structure of a new heterocyclic system – 7,8-dihydroimidazo- [1,2-c][1,3]thiazolo[4,5-e]pyrimidine

Kozachenko

Шаблыкин

Василенко

et al. 2011

Chem Heterocycl Comp

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Keywords: 8-aroylamino-1,2,3,7-tetrahydroimidazo[1,2-c]pyrimidines, phosphorus pentasulfide, polyphosphoric acid, triethyl orthoformate, heterocyclization.N-(2-Amino-1-imidazolidin-2-ylidene-2-thioxoethyl)arylamides 1 (see Scheme), synthesized from available 2-acylamino-3,3-dichloroacrylonitriles [1], were used previously to obtain the new heterocyclic system 4,5,7,It was shown in the present study that compounds 1 may be applied in the synthesis of one more new heterocyclic system 3, viz. 7,8-dihydroimidazo[1,3-c][1,3]thiazolo[4,5-e]pyrimidine. In difference to the preparation of the 7,8-dihydroimidazo[1,2-c][1,3]oxazolo[4,5-e]pyrimidine system in [3], in the present case a different method of design of the tricyclic heterocyclic system was used, the key stage of which was not the formation of the pyrimidine ring but annelation of the five-membered ring to a tetrahydroimidazo[1,2-c]pyrimidine fragment. First, compounds 1a-c were condensed with triethyl orthoformate with the formation of the previously unknown 8-aroylamino-7-thioxo-1,2,3,7-tetrahydroimidazo[1,2-c]pyrimidines 2a-c (Scheme and Table 1).Similar heterocyclizations of compounds with the characteristic fragment NH C C C(S)NH 2 were described previously in [4,5], but the products of such reactions are as a rule monocyclic derivatives of pyrimi-

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“…Compound (2) was obtained as colorless oil. It was assigned the same molecular formula C 17 H 20 O 3 as 1 by HRESIMS (m/z 273.1488 [MþH] þ ).…”

Section: Resultsmentioning

confidence: 99%

Eight new polyketide metabolites from the fungus Pestalotiopsis vaccinii endogenous with the mangrove plant Kandelia candel (L.) Druce

Wang

Wei

et al. 2014

Tetrahedron

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9-Arylpurines as a Novel Class of Enterovirus Inhibitors

Cited by 29 publications

References 41 publications

Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

Synthesis and structure of a new heterocyclic system – 7,8-dihydroimidazo- [1,2-c][1,3]thiazolo[4,5-e]pyrimidine

Eight new polyketide metabolites from the fungus Pestalotiopsis vaccinii endogenous with the mangrove plant Kandelia candel (L.) Druce

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