Molecular cloning and radioligand binding characterization of the chemokine receptor CCR5 from rhesus macaque and human

Napier, Carolyn; Sale, Harriet; Mosley, Michael; Rickett, Graham; Dorr, Pat; Mansfield, Roy; Holbrook, Mark

doi:10.1016/j.bcp.2005.10.024

Cited by 42 publications

(22 citation statements)

References 36 publications

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“…Preclinical toxicology studies also contradict a mechanismbased toxicity. Like other CCR5 antagonists (19), APL binds to macaque CCR5 but not to CCR5 from other species in preclinical studies; the fact that hepatotoxicity was detected in rats but not monkeys supports the theory that hepatotoxicity was more likely compound related rather than due to the effects of CCR5 antagonism.…”

Section: Discussionmentioning

confidence: 72%

Hepatotoxicity Observed in Clinical Trials of Aplaviroc (GW873140)

Nichols

Steel

Bonny

et al. 2008

Antimicrob Agents Chemother

146

100

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Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.

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Section: Discussionmentioning

confidence: 72%

Hepatotoxicity Observed in Clinical Trials of Aplaviroc (GW873140)

Nichols

Steel

Bonny

et al. 2008

Antimicrob Agents Chemother

146

100

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“…These data were confirmed by another group who also showed that CCR5 could bind the chemokines CCL7 and HCC-1 (CCL14), although the biologic activity of the chemokines was not assessed (Napier et al, 2005). CCL11 also has some biologic activity at CCR5, although very high concentrations (1 mM) were needed to induce a response (Ogilvie et al, 2001).…”

Section: E Ccr5mentioning

confidence: 70%

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

2013

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“…MVC and CMPD167 were slightly less active against virus replication in macaque than human PBMC, with CMPD167 being the marginally more potent inhibitor (Table 1). 3 H-MVC binding assays yielded mean equilibrium dissociation constant (K D ) values of 1.36 and 0.86 nM for macaque and human CCR5, respectively, although the inhibitor dissociated ϳ10-fold more quickly from macaque CCR5 (30). The IC 50 s for MVC inhibition of chemokine binding to macaque and human CCR5 were 17.5 and 7.2 nM (30); for CMPD167 they are 7.5 and 4.5 nM (M. Springer, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Malcolm

Veazey

Geer

et al. 2012

Antimicrob Agents Chemother

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e Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 g/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ϳ10 6 -fold greater than the 50% inhibitory concentrations (IC 50 s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

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Molecular cloning and radioligand binding characterization of the chemokine receptor CCR5 from rhesus macaque and human

Cited by 42 publications

References 36 publications

Hepatotoxicity Observed in Clinical Trials of Aplaviroc (GW873140)

Hepatotoxicity Observed in Clinical Trials of Aplaviroc (GW873140)

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

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