Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

Strizki, Julie; Tremblay, Cécile; Xu, Serena; Wojcik, Lisa; Wagner, Nicole; Gonsiorek, Waldemar; Hipkin, R. William; Chou, Chuan‐Chu; Pugliese-Sivo, Catherine; Xiao, Yuan; Tagat, Jayaram R.; Cox, Kathleen; Priestley, Tony; Sorota, Steve; Huang, Wei; Hirsch, Martin S.; Reyes, Gregory R.; Baroudy, Bahige M.

doi:10.1128/aac.49.12.4911-4919.2005

Cited by 200 publications

(122 citation statements)

References 27 publications

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“…The three clade G isolates tested (RU570, JV1083, and G3) presented the highest EC 50 values, in agreement with previous reports demonstrating reduced sensitivity of clade G viruses to VCV (18,19). In the presence of RAPA concentrations of 0.1, 0.3, and 1 nM, VCV EC 50 values were reduced by up to 7.5-, 10-, and 60-fold, respectively.…”

Section: Rapa Enhances the Antiviral Activity Of Vcv Against R5 Hiv-1supporting

confidence: 78%

“…RAPA enhanced VCV antiviral activity against primary strains of both B and non-B clades. Of note, the combination of RAPA and VCV was especially potent against clade G isolates, which have reduced sensitivities to VCV (19) and maraviroc (18). At a concentration of 1 nM, RAPA reduced VCV EC 50 values by 30-to 60-fold against the tested clade G isolates.…”

Section: Discussionmentioning

confidence: 99%

“…The experiments described in the previous paragraphs were conducted using the HIV-1 clade B strains JRFL and CC1/85, which have been used frequently in studies evaluating entry inhibitors (18,19). Because of the remarkable variability in sequence diversity among HIV-1 clades, we also evaluated the antiviral activity of RAPA/VCV in viruses from non-B clades.…”

Section: Rapa Enhances the Antiviral Activity Of Vcv Against R5 Hiv-1mentioning

confidence: 99%

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Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Heredia

Latinovic

Gallo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Vicriviroc (VCV) is a chemokine (C-C motif) receptor 5 (CCR5)antagonist with potent anti-HIV activity that currently is being evaluated in phase III clinical trials. In the present study, donor CCR5 density (CCR5 receptors/CD4 lymphocytes) inversely correlated with VCV antiviral activity (Spearman's correlation test; r ‫؍‬ 0.746, P ‫؍‬ 0.0034). Low doses of the transplant drug rapamycin (RAPA) reduced CCR5 density and enhanced VCV antiviral activity. In drug interaction studies, the RAPA/VCV combination had considerable antiviral synergy (combination indexes of 0.1-0.04) in both multicycle and single-cycle infection of lymphocytes. The synergy between RAPA and VCV translated into dose reduction indexes of 8-to 41-fold reductions for RAPA and 19-to 658-fold reductions for VCV. RAPA enhanced VCV antiviral activity against both B and non-B clade isolates, potently suppressing clade G viruses with reported reduced sensitivities to VCV and to the licensed CCR5 antagonist maraviroc. Importantly, RAPA reduction of CCR5 density in lymphocytes sensitized VCV-resistant strains to VCV, inhibiting virus production by ϳ 90%. We further demonstrated the role of CCR5 density on VCV activity against resistant virus in donor lymphocytes and in cell lines expressing varying CCR5 densities. Together, these results suggest that low doses of RAPA may increase the durability of VCV-containing regimens in patients by enhancing VCV viral suppression, by allowing the use of lower doses of VCV with reduced potential for toxicity, and by controlling emerging VCV-resistant variants.chemokine receptor 5 antagonists ͉ coreceptor density ͉ HIV resistance ͉ vicriviroc resistance ͉ maraviroc H ighly active antiretroviral therapy (HAART) has improved treatment of HIV-1 infected individuals considerably (1). However, the success of current therapies is limited by the emergence of drug-resistant strains, the need for sustained adherence to complex regimens, and the potential for drug toxicity (2, 3). The two new antiretroviral classes of integrase and entry inhibitors may help overcome some of the current limitations of HAART (4, 5). Entry inhibitors are especially attractive because they target HIV at the earliest step of the viral cycle and are effective against strains resistant to inhibitors of protease and reverse transcriptase. Entry inhibitors interfere with HIV binding to CD4 receptor (attachment inhibitors) or chemokine (C-C motif) receptor 5 (CCR5)/chemokine (C-X-C-motif) receptor 4 (CXCR4) coreceptors (coreceptor antagonists) or by preventing fusion between cellular and viral membranes (fusion inhibitors) (5). Currently, the fusion inhibitor T-20 (enfuvirtide) and the CCR5 antagonist maraviroc (Selzentry) are the only licensed entry inhibitors (6, 7). The CCR5 antagonist vicriviroc (VCV) presently is in phase III clinical trials (8). Coreceptor CCR5 antagonists inhibit CCR5-tropic HIV-1 (referred to as ''R5 HIV-1'') strains, which are responsible for most transmissions and generally are present throughout the course of infection. In nor...

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Section: Rapa Enhances the Antiviral Activity Of Vcv Against R5 Hiv-1supporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Rapa Enhances the Antiviral Activity Of Vcv Against R5 Hiv-1mentioning

confidence: 99%

See 1 more Smart Citation

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Heredia

Latinovic

Gallo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…[7][8][9][10]50 Currently, there are a number of chemokine receptor antagonists under review. 40,41,[51][52][53] An alternative therapeutic method for disrupting HIV entry is the use of gene delivery to provide a genetic means to alter expression or block the function of chemokine receptors, for example, intrabodies, ribozymes, intrakines, zinc-fingers or RNAi. [13][14][15][16]54 Our approach to disrupting CCR5 expression on the cell surface relies on cellular expression of a humanized intrabody targeting CCR5.…”

Section: Discussionmentioning

confidence: 99%

T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery

et al. 2006

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CCR5 is the chemokine co-receptor for R5-tropic human immunodeficiency virus type 1 (HIV-1) isolates most often associated with primary infection. We have developed an HIV-1 self-inactivating vector, CAD-R5, containing a CCR5 single-chain antibody (intrabody) gene, which when expressed in T-cell lines and primary CD4 + T cells disrupts CCR5 cell surface expression and provides protection from R5-tropic isolate exposure. Furthermore, CAD-R5 intrabody expression in primary CD4 + T cells supports significant growth and enrichment over time during HIV-1-pulsed dendritic cell-T-cell interactions. These results indicate that CCR5 intrabody-expressing CD4 + T cells are refractory against this highly efficient primary route of infection. CD34 + cells transduced with the CAD-R5 vector gave rise to CD4 + and CD8 + thymocytes in non-obese diabetic (NOD)/ severely combined-immunodeficient (SCID)-human thymus/ liver (hu thy/liv) mice, suggesting that CCR5 intrabody expression can be maintained throughout differentiation without obvious cellular effects. CD4 + T cells isolated from NOD/SCID-hu thy/liv mice were resistant to R5-tropic HIV-1 challenge demonstrating the maintenance of protection. Our findings demonstrate delivery of anti-HIV-1 activity through CCR5 intrabodies in primary CD4 + T cells and CD34 + cell-derived T-cell progeny. Thus, gene delivery strategies that provide a selective survival and growth advantage for T effector cells may provide a therapeutic benefit for HIV-1-infected individuals who have failed conventional therapies.

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“…As detailed elsewhere [38][39][40][41], urine was collected in block intervals for 10 d following a single 50 mg administration of 14 C-VCV (ϳ100 Ci) to six healthy volunteers. This was a Phase I open-label study designed to characterize the absorption, metabolism, and excretion of 14 C-VCV.…”

Section: Methodsmentioning

confidence: 99%

Response normalized liquid chromatography nanospray ionization mass spectrometry

Ramanathan¹,

Zhong²,

Blumenkrantz³

et al. 2007

J. Am. Soc. Mass Spectrom.

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The widely different LC-MS response observed for many structurally different compounds limits the use of LC-MS in full scan detection mode for quantitative determination of drugs and metabolites without using reference standard. The recently introduced nanospray ionization (NSI) technique shows comparable MS response for some compounds under non-LC-MS conditions. However, in the presence of numerous endogenous compounds commonly associated with biological samples such as urine, plasma, and bile, LC-MS is required to separate, detect, identify, and measure individual analytes. An LC-NSI-MS system was devised and the MS response obtained in this system for a variety of pharmaceutical drugs and their metabolites. The set-up involves two high-performance liquid chromatography (HPLC) systems, a chip-based NSI source and a quadrupole-time-of-flight (Q-TOF) mass spectrometer. Herein this is referred to as the response normalized-liquid chromatography NSI-MS (RNLC-NSI-MS) system. One HPLC unit performs the analytical separation, while the other unit adds solvent post-column with an exact reverse of the mobile phase composition such that the final composition entering the NSI source is isocratic throughout the entire HPLC run . LC-MS/MS techniques for quantitation require reference and internal standard(s), so that LC-MS/MS responses from unknown quantities of relevant drug-related peaks can be related back to responses obtained using known quantities of each analyte. Usually a standard curve is generated for each and every analyte to be quantified [6]. Although reference standards may be available for the parent drug, it is very unlikely to have standards for metabolites available in early stage of drug discovery and development thereby making conventional LC-MS/MS based quantitation of metabolites impractical.Nanospray ionization (NSI), introduced by Wilm and Mann in the 1990s [8], has been used to identify proteins [9 -13] and drug metabolites [14], quantify pharmaceutical drugs [15,16], study absorption, distribution, metabolism and excretion (ADME) properties of drugs [17], and employed in various other applications [12, 13, 15, 16, 18 -34]. NSI-MS has the following advantages over conventional flow ESI-MS: (1) higher sensitivity, (2) lower rate of sample consumption, and (3) improved signal-to-noise ratio (S/N). Although both on-and off-line NSI-MS have been developed, off-line NSI-MS methods have been more frequently used because of the technical difficulties associated with interfacing conventional flow LC systems with NSI and

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Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

Abstract: Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors

Cited by 200 publications

References 27 publications

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery

Response normalized liquid chromatography nanospray ionization mass spectrometry

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