Thiourea inhibitors of herpes viruses. part 1: bis-(aryl)thiourea inhibitors of CMV

Bloom, Jonathan D.; DiGrandi, Martin J.; Dushin, Russell G.; Curran, Kevin J.; Ross, Adma A.; Norton, Emily B.; Terefenko, Eugene A.; Jones, Thomas R.; Feld, Boris; Lang, Stanley A.

doi:10.1016/s0960-894x(03)00586-9

Cited by 49 publications

(32 citation statements)

References 16 publications

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“…CFI02 belongs to a novel series of small molecule HCMV inhibitors for which structure-activity relationship has recently been determined (3). Futhermore, the viral target FIG.…”

Section: Discussionmentioning

confidence: 99%

“…A screening hit with low-level activity against HSV was identified that was not active against HCMV (3,56). Initial synthetic chemistry efforts yielded a related bis-aryl thiourea compound with a low micromolar 50% inhibitory concentration (IC 50 ) against HCMV (CFI01) (Fig.…”

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confidence: 99%

“…CFI02 (molecular weight ϭ 491; Fig. 1B) is a representative molecule from this recently described series that specifically inhibits HCMV (compound 38 in Bloom et al [3]). We show here that a target of CFI02 is inhibition of HCMV glycoprotein B (gB)-mediated fusion of the virion envelope with the cellular plasma membrane.…”

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confidence: 99%

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Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Jones

Lee²,

Johann³

et al. 2004

J Virol

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A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.

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“…CFI02 belongs to a novel series of small molecule HCMV inhibitors for which structure-activity relationship has recently been determined (3). Futhermore, the viral target FIG.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Jones

Lee²,

Johann³

et al. 2004

J Virol

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“…In this regard, potent and selective inhibitors of cytomegalovirus (CMV) (17), Varicella-zoster virus (VZV) (18), and herpes simplex virus type-1 (HSV-1) (19)(20)(21) were developed (Figure 3). In our previous work on thiourea derivatives (1), we reported the synthesis and antiviral evaluation of N-phenyl-N´-{4-[ (4-allyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy]phenyl}thiourea which showed moderate protection against Coxsackie virus B4 with an MIC value of 16 µg/ml (40.25 µM, SI=5) and thymidine kinase wild-type varicella-zoster virus (TK + VZV, OKA strain) with an EC 50 value of 9.9 µg/ml (Figure 3).…”

Section: Tatar Et Al Heterocyclic Derivatives Of L-methioninementioning

confidence: 99%

Synthesis and biological evaluation of some new 1,3,4-thiadiazole and 1,2,4-triazole derivatives from L-methionine as antituberculosis and antiviral agents

Tatar

Küçükgüzel²,

Karakuş³

et al. 2015

mpj

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Some novel 1,3,4-thiadiazole [5][6][7][8] and 1,2,4-triazole [9][10][11][12] derivatives carrying amino acid moiety were synthesized starting from L-methionine. 1,3,4-Thiadiazole and 1,2,4-triazole scaffolds were prepared by cyclocondensation of the corresponding thiosemicarbazide and finally converted to their thiourea derivatives. Structures of the synthesized compounds [4][5][6][7][8][9][10][11][12] were confirmed by IR, 1 H-NMR and 13 C-NMR spectral data and elemental analysis.

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“…To characterize the role of virion fusion in HCMV-mediated ISG induction, an HCMV-specific fusion inhibitor, CFI02, was used (2). It was previously shown that this inhibitor has no effect on the attachment of virus to cells, but that it efficiently blocks subsequent viral-cell fusion at a 2 M concentration (7).…”

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Postattachment Events Associated with Viral Entry Are Necessary for Induction of Interferon-Stimulated Genes by Human Cytomegalovirus

Netterwald

Jones

Britt

et al. 2004

J Virol

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Utilizing a human cytomegalovirus-specific fusion inhibitor and an antiglycoprotein H antibody, we studied the role of virion fusion in interferon-stimulated gene (ISG) induction. Our results indicate that ISG induction does not occur when virion-mediated, post-high-affinity attachment events are inhibited by either reagent. Thus, virion-mediated postattachment events, such as fusion, are required for ISG induction.A large number of interferon-stimulated genes (ISGs) are strongly activated following human cytomegalovirus (HCMV) infection (19). In early studies, UV-irradiated HCMV was shown to induce ISGs (19). Subsequent studies revealed that virion envelope proteins, specifically glycoprotein B (gB), were responsible for the induction of ISGs (3,17). Soluble gB applied to human fibroblasts resulted in the induction of ISGs. Because the latter experiment was done under nonphysiological conditions and because gB has been shown to have roles in both virion attachment and fusion, it was unclear whether virion attachment alone was sufficient to induce ISG expression. Alternatively, other HCMV envelope glycoproteins or perhaps the fusion process itself is required for ISG activation during natural infection, as is the case for ISG induction by herpes simplex virus (14). In this study, we examined the requirement of postattachment steps of HCMV entry for the induction of ISGs.To characterize the role of virion fusion in HCMV-mediated ISG induction, an HCMV-specific fusion inhibitor, CFI02, was used (2). It was previously shown that this inhibitor has no effect on the attachment of virus to cells, but that it efficiently blocks subsequent viral-cell fusion at a 2 M concentration (7). CFI02 was used to determine if the compound also blocks induction of ISGs by HCMV (Fig. 1A). Human foreskin fibroblast (HFF) cells were either mock infected or infected with HCMV in the presence of dimethyl sulfoxide (control) or CFI02 for 8 h. Induction of the ISGs isg54K and cig49 was determined by RNA blot analysis. A cellular pseudogene, 7SK (13), was used as an internal control. Induction of ISGs by HCMV was inhibited in the presence of CFI02 (Fig. 1A, compare lanes 2 and 3). These results indicated that a postattachment step of HCMV infection, presumably virion fusion with the cellular membrane, was required for the induction of ISG expression. The effect of CFI02 inhibition on HCMV fusion was specific because (i) it had no effect on CFI02-resistant, HCMV-mediated ISG induction (the resistance phenotype was mapped to gB) (7) (lanes 4 and 5); (ii) it did not block murine-CMV-mediated ISG induction (lanes 9 and 10); (iii) it had no effect on alpha interferon (IFN-␣)-induced ISG expression (lanes 6 and 7); and (iv) it was not able to block induction of ISGs when added 2 h after infection (lanes 3 and 8). Furthermore, inhibition of HCMV-induced ISG expression by CFI02 had no effect on IFN-␣-mediated induction of ISGs (lanes 11 and 12). In addition, as shown previously (19), HCMV is able to induce isg54K at 12 and 24 h postinfection (hpi)...

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Thiourea inhibitors of herpes viruses. part 1: bis-(aryl)thiourea inhibitors of CMV

Cited by 49 publications

References 16 publications

Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Specific Inhibition of Human Cytomegalovirus Glycoprotein B-Mediated Fusion by a Novel Thiourea Small Molecule

Synthesis and biological evaluation of some new 1,3,4-thiadiazole and 1,2,4-triazole derivatives from L-methionine as antituberculosis and antiviral agents

Postattachment Events Associated with Viral Entry Are Necessary for Induction of Interferon-Stimulated Genes by Human Cytomegalovirus

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