Species selectivity of small-molecular antagonists for the CCR5 chemokine receptor

Saita, Yuji; Kondo, Mitsuhiro; Shimizu, Yoshiyuki

doi:10.1016/j.intimp.2007.07.019

Cited by 19 publications

(11 citation statements)

References 27 publications

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“…Because maraviroc does not bind to murine CCR5 21-23 , we used CCR5 knock-in mice expressing human CCR5 (h-CCR5ki) for pharmacological studies and immunohistochemical analyses of CCR5-expressing cells. After 18 days of hypoxia, the h-CCR5ki mice had similar PH severity to that in WT mice and showed large increases in lung CCR5 protein levels (Figure 4A) and CCR5 staining in the PA-SMC layer of remodeled vessels (Figure 4B), whereas CCR5 staining in PA-ECs and macrophages was less affected by PH development (Figure 4C and D).…”

Section: Resultsmentioning

confidence: 99%

“…To this end, we used several approaches: we evaluated CCR5 expression and localization in lung tissue from patients with PH; CCR5 −/− mice exposed to chronic hypoxia; and the effect of maraviroc-induced CCR5 inhibition on PH induced in mice by exposure to chronic hypoxia or SU5416/hypoxia. For these studies, we used CCR5 knock-in mice expressing human CCR5, as maraviroc does not bind to murine CCR5 21-23 and we also conducted cell studies in bone marrow (BM)-chimeric mice generated from CCR5 −/− and wild-type (WT) mice, to investigate whether the CCL5-CCR5 pathway led to PH through direct effects on pulmonary vascular cells or through cross-talk between macrophages and pulmonary-artery smooth muscle cells (PA-SMCs).…”

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confidence: 99%

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CCR5 as a Treatment Target in Pulmonary Arterial Hypertension

et al. 2014

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Background Pulmonary arterial hypertension (PH), whether idiopathic or related to underlying diseases such as HIV infection, results from complex vessel remodeling involving both pulmonary-artery smooth muscle cell (PA-SMC) proliferation and inflammation. CCR5, a co-receptor for cellular HIV-1 entry expressed on macrophages and vascular cells, may be involved in the pathogenesis of PH. Maraviroc is a new CCR5 antagonist designed to block HIV entry. Methods and Results Marked CCR5 expression was found in lungs from patients with idiopathic PH, in mice with hypoxia-induced PH and in SIV-infected macaques, in which it was chiefly localized in the PA-SMCs. To assess the role for CCR5 in experimental PH, we used both gene disruption and pharmacological CCR5 inactivation in mice. Because maraviroc does not bind to murine CCR5, we used human-CCR5ki mice for pharmacological and immunohistochemical studies. Compared to wild-type mice, CCR5−/− mice or human-CCR5ki mice treated with maraviroc exhibited decreased PA-SMC proliferation and recruitment of perivascular and alveolar macrophages during hypoxia exposure. CCR5−/− mice reconstituted with wild-type bone-marrow cells and wild-type mice reconstituted with CCR5−/− bone-marrow cells were protected against PH, suggesting CCR5-mediated effects on PASMCs and macrophage involvement. The CCR5 ligands CCL5 and the HIV-1 gp120 protein increased intracellular calcium and induced growth of human and h-CCR5ki mouse PASMCs; maraviroc inhibited both effects. Maraviroc also reduced the growth-promoting effects of conditioned media from CCL5-activated macrophages derived from human-CCR5ki mice on PA-SMCs from wild-type mice. Conclusions The CCL5-CCR5 pathway represents a new therapeutic target in PH associated with HIV or with other conditions.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

CCR5 as a Treatment Target in Pulmonary Arterial Hypertension

et al. 2014

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“…Yet because many new-generation microbicides being considered contain antiretrovirals that often exhibit exquisite specificity for HIV, multiple SIV/SHIV macaque models need to be developed for efficacy testing in vivo (20,27,28,38,46,50,52). Furthermore, within different NHP models there are differences in viral (i.e., HIV versus SHIV envelope variable region 3) and host (i.e., human versus macaque CCR5) sequences, resulting in distinctions that preclude the use of certain HIV-specific inhibitors and can confound the interpretation of the data obtained (4,33,42,49). These factors together with the expense of NHP testing and the limited availability of female animals have severely limited their broad utilization in the evaluation of novel HIV prevention interventions.…”

Section: Vol 85 2011mentioning

confidence: 99%

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Denton

Othieno

Martinez-Torres

et al. 2011

J Virol

130

150

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“…[131] Another illustration involves TAK-779, which has a 100-fold higher affinity for human CCR5 than for mouse CCR5, complicating interpretation of the results from murine studies. [73,132] A careful inspection of all available results on CXCR3 points towards some species differences, caused by differences in the protein sequence of CXCR3 from various species. Compound 27 has affinities of 16 and 227 nm for human and murine CXCR3 ([ 35 S]-GTPgS), [102] respectively, whereas some compounds of the related later-stage tropanyl class reveal a 3-4-fold preference for human CXCR3.…”

Section: Modulation Of Cxcr3 By Nonpeptidergic a C H T U N G T R E N mentioning

confidence: 99%

Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

et al. 2008

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The CXCR3 chemokine receptor was first discovered in 1996 and has been shown to play an important role in several diseases, most of which are related to inflammation. This review describes in detail the development of small CXCR3 ligands and their therapeutic potential. Classes of CXCR3 antagonists with strikingly variable core structures have emerged. Some of these compounds have confirmed the beneficial role of CXCR3 antagonism in animal models of disease. One of the compounds, AMG487, progressed to Phase II clinical trials but has been withdrawn because of lack of efficacy. New antagonist classes are being developed to reveal the full therapeutic potential of CXCR3.

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Species selectivity of small-molecular antagonists for the CCR5 chemokine receptor

Cited by 19 publications

References 27 publications

CCR5 as a Treatment Target in Pulmonary Arterial Hypertension

CCR5 as a Treatment Target in Pulmonary Arterial Hypertension

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

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