Substituted benzocyloheptenes as potent and selective αv integrin antagonists

Perron-Sierra, Françoise; Dizier, Dominique Saint; Bertrand, Marc; Genton, Annie; Tucker, Gordon C.; Casara, Patrick

doi:10.1016/s0960-894x(02)00696-0

Cited by 42 publications

(35 citation statements)

References 39 publications

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“…The compounds tested comprised three structurally unrelated potent inhibitors of a v b 3 and a v b 5 integrins (S36578 and compounds C1 and C3), together with five inhibitors related to S36578 (compounds C2 and C4 to C7) identified during structure-activity studies, with various potencies (13). They were all able to block HIV replication with different efficacies, depending on their affinity toward the corresponding integrins in binding assays (Table I).…”

Section: Differential Expression Of a V -Coupled B Integrins In Macromentioning

confidence: 99%

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Ballana

Pauls

Clotet

et al. 2011

The Journal of Immunology

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Monocytes and macrophages are targets of HIV-1 infection and play critical roles in multiple aspects of viral pathogenesis. During the differentiation of monocytes to macrophages, adhesion molecules such as integrins are upregulated; therefore, they provide signals that control the process and subsequently may render macrophages more susceptible to HIV-1 infection. Previous work demonstrated that blocking αv-containing integrins triggered a signal transduction pathway leading to the inhibition of NF-κB–dependent HIV-1 transcription. In this paper, we show the influence of the different αv-coupled β integrins in HIV-1 replication in macrophages. Inhibition of β integrins, either by specific mAbs, small arginine-glycine-aspartic acid (RGD) mimetic compounds, or RNA interference, showed that integrin β5 was the major contributor to the integrin-mediated blockade of HIV-1 replication. Importantly, such inhibition did not induce changes in cell adhesion to the substrate. In conclusion, our results reveal a significant role of the integrin dimmer αvβ5 in HIV-1 infection of macrophages.

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Section: Differential Expression Of a V -Coupled B Integrins In Macromentioning

confidence: 99%

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Ballana

Pauls

Clotet

et al. 2011

The Journal of Immunology

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“…Other compounds, derived from the S36578 series, 21 were also tested for their capacity to inhibit HIV-1 replication in MDMs. A correlation between their anti-HIV activity and the capacity to inhibit integrin binding in cell adhesion assays in vitro was observed, confirming the ␣V-dependent specificity of the anti-HIV effect (data not shown).…”

Section: Drug-mediated Blockade Of ␣V Inhibits Hiv-1 Replication In Mdmsmentioning

confidence: 99%

“…-butyrylamino]-methyl}-6,9-dihydro-5H-benzocyclohepten-5-yl) acetic acid (compound 1.2, synthesized as described by Perron-Sierra et al 21 ) is a selective small heterocyclic RGD-mimetic nonpeptide compound targeting ␣V␤3 and ␣V␤5 integrins. 21,22 The RT inhibitor 3-azido-3-deoxythymidine (zidovudine; AZT) was purchased from Sigma-Aldrich, CCR5 antagonist TAK-779 (reviewed by Este and Telenti 23 ) and AMD3100 were received from the National Institutes of Health AIDS Reagent Program, and the HIV integrase inhibitor L-731988 was obtained from Merck (Rahway, NJ).…”

Section: S36578 (5-(s)-7-{[4-(pyridin-2-ylamino)mentioning

confidence: 99%

“…21,22 The RT inhibitor 3-azido-3-deoxythymidine (zidovudine; AZT) was purchased from Sigma-Aldrich, CCR5 antagonist TAK-779 (reviewed by Este and Telenti 23 ) and AMD3100 were received from the National Institutes of Health AIDS Reagent Program, and the HIV integrase inhibitor L-731988 was obtained from Merck (Rahway, NJ). 24 Phorbol 12-myristate 13-acetate (PMA) was purchased from Sigma-Aldrich and tumor necrosis factor ␣ (TNF-␣) from PeproTech.…”

Section: S36578 (5-(s)-7-{[4-(pyridin-2-ylamino)mentioning

confidence: 99%

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Cell adhesion through αV-containing integrins is required for efficient HIV-1 infection in macrophages

Ballana

Pauls

Senserrich

et al. 2009

Blood

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IntroductionIntegrins are a family of transmembrane cell adhesion receptors that recognize cell-surface and extracellular matrix ligands. 1 All integrins are heterodimers composed of noncovalently linked ␣ and ␤ subunits. In humans, at least 18 ␣ and 8 ␤ subunits have been identified, forming more than 20 heterodimers, each of them with different cell expression patterns and ligand specificities. 2 Integrinmediated interactions are vital to the maintenance of normal cell functioning, as they mediate the interaction between cells and with the extracellular matrix, having therefore important implications for cell adhesion, migration, and proliferation. Integrins function as mediators for cell-cell interaction and adhesion but may also elicit signal transduction events leading to cell activation and response to the extracellular stimulus. 1 Different enveloped and nonenveloped viruses use integrins to enter and replicate in host cells. 3 Integrins may act as viral receptors that mediate virus attachment to the cell, a process that may also promote signaling responses influencing viral replication at a later step. In the case of human cytomegalovirus, ␣V␤3 has been described as an entry coreceptor but also as a trigger-mediator of intracellular signaling pathways. 4 The ␣4␤7 integrin, preferentially expressed in activated T cells homing to the gut, may interact with the HIV-1 envelope glycoprotein gp120, leading to increased virus replication. 5 Human blood monocytes, originated from hematopoietic precursors in the bone marrow, give rise to mature macrophages, which are distributed ubiquitously in all tissues. 6,7 Adhesion molecules, particularly integrins, have been shown to up-regulate when monocytes differentiate into macrophages, [8][9][10] suggesting that integrins play an important role in macrophage adhesion, migration, and tissue infiltration. Blood monocytes and tissue resident macrophages are important in vivo cell targets of HIV-1 infection. [11][12][13] Macrophages may become chronically infected or serve as reservoirs of latent virus. Furthermore, HIV may sequester macrophage immunoregulatory function, that is, inducing secretion of proinflammatory cytokines that lead to recruitment and activation of new target cells for HIV, including CD4 ϩ T cells. 14,15 Unlike monocyte-derived macrophages (MDMs), undifferentiated monocytes are not readily infected by HIV-1 in cell culture. 16,17 A productive viral infection may only occur after monocytes are differentiated after serum or cytokine stimulation, 18 a process that leads to the up-regulation of different cell-surface markers and receptors, including ␣V integrins 19,20 and, more specifically, an increase in the vitronectin ␣V␤3 receptor during the first 3 to 6 hours after infection. 14 We and others have shown the antiviral effect of specific anti-␣V antibodies in MDMs. 19,20 Here, we describe the involvement of ␣V integrin-mediated adhesion in HIV-1 replication of MDMs and HeLa cells. Our data support the idea that blocking integrin ␣V interaction with it...

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“…[9,10] These compounds, at micromolar concentrations, were shown to block cell migration, but recent work reported that lower concentrations of these drugs can actually enhance the growth of tumors in vivo by promoting migration and VEGF-mediated angiogenesis. [7] Other recent work has investigated the analogy between tumor angiogenesis and wound healing [3,11] with the finding that the fibronectin-derived Pro-His-SerArg-Asn (PHSRN) peptide can stimulate migration of human kerotinocytes and fibroblasts and accelerate wound healing in obese diabetic mice.…”

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confidence: 99%

An Inhibitor of a Cell Adhesion Receptor Stimulates Cell Migration

2010

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The integrins are a family of heterodimeric receptors that play a universal role in mediating the adhesion of cells to the extracellular matrix. As such, the differential interactions of the receptors at the front and back ends of the cell are important in regulating the migration of cells. [1] Approximately one-half of the integrins recognize the canonical RGD motif found in fibronectin, and a significant body of work has shown that model substrates presenting the RGD peptide support the adhesion and migration of cells. [2] Inhibitors of the integrin receptor have been explored as reagents that may block cell migration and recent work has advanced a class of soluble RGD peptides as possible therapeutics that display anti-metastatic activity. [3][4][5] But the molecular mechanisms by which these compounds block migration have not been elucidated and have recently been contradicted by work that demonstrates that the soluble antagonists can also promote the migration of tumor cells. [6][7][8] Herein, we use a well-defined model system to assess the influence of soluble inhibitors on cell migration and we show that the integrin antagonists are able to promote the migration of cells.The RGD-mimetic compounds cilengitide and S36578 were developed as integrin antagonists and are now in early phase clinical trials for cancer therapy. [9,10] These compounds, at micromolar concentrations, were shown to block cell migration, but recent work reported that lower concentrations of these drugs can actually enhance the growth of tumors in vivo by promoting migration and VEGF-mediated angiogenesis. [7] Other recent work has investigated the analogy between tumor angiogenesis and wound healing [3,11] with the finding that the fibronectin-derived Pro-His-SerArg-Asn (PHSRN) peptide can stimulate migration of human kerotinocytes and fibroblasts and accelerate wound healing in obese diabetic mice. [8] Our group [12,13] and others [14] have suggested that PHSRN antagonizes RGD binding, and therefore may accelerate migration by inhibiting the integrinmediated adhesion. Additionally, it has been reported that addition of insulin-like growth factor binding protein (IGFBP-1) which contains the RGD sequence in the cell culture medium increases the migration of CHO cells twofold compared to cells treated with Trp-Gly-Asp (WGD). [6] The literature contains several additional contradictory reports as to the effect of soluble RGD-containing proteins on adhesion and migration. [5,15] Mechanistic studies of the roles of ligand-receptor interactions in cell migration are challenging because it is difficult to control which interactions operate between cell and matrix. This limitation is particularly relevant to in vivo experiments, where a broad range of signals and matrix constituents are present and not always defined. [16] Even in the laboratory, it can be difficult to reproducibly present matrix ligands to a cell in order to obtain reproducible matrix formulations. [5] To address these limitations, we use selfassembled monolayers that presen...

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Substituted benzocyloheptenes as potent and selective αv integrin antagonists

Cited by 42 publications

References 39 publications

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

β5 Integrin Is the Major Contributor to the αv Integrin-Mediated Blockade of HIV-1 Replication

Cell adhesion through αV-containing integrins is required for efficient HIV-1 infection in macrophages

An Inhibitor of a Cell Adhesion Receptor Stimulates Cell Migration

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