Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28

Hulshof, Janneke W.; Vischer, Henry F.; Verheij, Mark H.P.; Fratantoni, Silvina A.; Smit, Martine J.; Esch, Iwan J. P. de; Leurs, Rob

doi:10.1016/j.bmc.2006.06.054

Cited by 35 publications

(23 citation statements)

References 49 publications

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“…Double alkylation of (4-chlorophenyl)acetonitrile 35 with the nitrogen mustard bis-(2-chloroethyl)carbamic acid tert-butyl ester 45 gave the common intermediate nitrile 36. 46 Reduction of the nitrile 36 with Raney nickel produced the 4-chlorophenyl-4-aminomethylpiperidine fragment 37 from which compounds 17-19 were prepared using the displacement reactions described before. Alternatively, the intermediate nitrile 36 was hydrolyzed to the carboxylic acid 38.…”

Section: Methodsmentioning

confidence: 99%

Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration

et al. 2008

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Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.

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Section: Methodsmentioning

confidence: 99%

Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration

et al. 2008

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“…In this report, we demonstrate that US28 and (to a lesser degree) UL33 restore reactivation from tissue explants and partially restore replication in salivary glands (compared to a signaling-deficient M33 mutant). These studies provide a novel small animal model for evaluation of therapies targeting the human CMV CKRs.Chemokine receptor (CKR) homologues and other seventransmembrane receptor (7TMR) homologues are characteristic of beta-and gammaherpesviruses and are potential therapeutic targets (7,14,16). Human cytomegalovirus (HCMV) encodes four 7TMRs: UL33 and UL78 are conserved in all betaherpesviruses, whereas US28/US27 homologues are restricted to primate betaherpesviruses.…”

mentioning

confidence: 99%

“…Chemokine receptor (CKR) homologues and other seventransmembrane receptor (7TMR) homologues are characteristic of beta-and gammaherpesviruses and are potential therapeutic targets (7,14,16). Human cytomegalovirus (HCMV) encodes four 7TMRs: UL33 and UL78 are conserved in all betaherpesviruses, whereas US28/US27 homologues are restricted to primate betaherpesviruses.…”

mentioning

confidence: 99%

Partial Functional Complementation between Human and Mouse Cytomegalovirus Chemokine Receptor Homologues

Farrell

Abraham

Cardin

et al. 2011

J Virol

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The human cytomegalovirus (CMV) proteins US28 and UL33 are homologous to chemokine receptors (CKRs). Knockout of the mouse CMV M33 protein (UL33 homologue) results in substantial attenuation of salivary gland infection/replication and reduced efficiency of reactivation from tissue explants. M33-mediated G protein-coupled signaling is critical for the salivary gland phenotype. In this report, we demonstrate that US28 and (to a lesser degree) UL33 restore reactivation from tissue explants and partially restore replication in salivary glands (compared to a signaling-deficient M33 mutant). These studies provide a novel small animal model for evaluation of therapies targeting the human CMV CKRs.Chemokine receptor (CKR) homologues and other seventransmembrane receptor (7TMR) homologues are characteristic of beta-and gammaherpesviruses and are potential therapeutic targets (7,14,16). Human cytomegalovirus (HCMV) encodes four 7TMRs: UL33 and UL78 are conserved in all betaherpesviruses, whereas US28/US27 homologues are restricted to primate betaherpesviruses.Clues to the roles of HCMV 7TMRs have come from in vivo studies of mouse and rat CMVs (MCMV and RCMV, respectively). Acute-phase replication in primary organs is followed by dissemination to secondary sites, such as salivary glands, where virus may replicate for several days, attaining high titers. Following immune clearance of productive infection, latently infected cells remain distributed in a number of organs. In the absence of M33 (UL33 homologue), MCMV failed to attain detectable levels of infectious virus in salivary glands, with similar observations for R33 of RCMV (1, 5), suggesting evolutionarily conserved functions. The mechanisms underlying salivary gland attenuation may include defects in dissemination to, initial infection of, or maintenance of productive infection within that organ. Definitive studies are lacking, but there is some evidence for attenuation at a postdissemination step; the M33-null mutant was defective for replication following direct intrasalivary gland inoculation, and the R33-null mutant was detectable in salivary glands (by PCR), similar to the wild type at early times postinfection (1, 5). We and others have demonstrated the importance of constitutive M33-induced signaling for the salivary gland phenotype (4, 15). We further demonstrated that an M33-null mutant was deficient for reactivation in an ex vivo tissue explant model (2), although whether M33 plays a specific role during the establishment of, maintenance of, or reactivation from latency is not yet known.

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“…Besides inhibiting US28-mediated signaling activity in transfected cells, VUF2274 could also reduce the constitutive activity of US28 observed in HCMV-infected cells [33]. Such inverse agonist compounds may be promising antiviral drugs, but further optimization and improvement of the affinity of these compounds is still required [60,61].…”

Section: The Rhadinovirus Genus: Hhv-8/kshvmentioning

confidence: 99%

Constitutively Active Viral Chemokine Receptors: Tools for Immune Subversion and Pathogenesis

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Bongers

Lira

et al. 2010

Methods and Principles in Medicinal Chemistry

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Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28

Cited by 35 publications

References 49 publications

Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration

Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration

Partial Functional Complementation between Human and Mouse Cytomegalovirus Chemokine Receptor Homologues

Constitutively Active Viral Chemokine Receptors: Tools for Immune Subversion and Pathogenesis

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