SEARCH · PubMed Health

Results for “Integrin alphaVbeta3”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed2006

Alphavbeta3-integrin imaging: a new approach to characterise angiogenesis?

OVERVIEW: The field of angiogenesis research is one of the most rapidly growing biomedical disciplines. Great efforts are being made to develop anti-angiogenesis drugs for treatment of cancer as well as non-oncological diseases. Thus, imaging techniques allowing non-invasive monitoring of corresponding molecular processes will be of great interest. One target structure involved in the angiogenic process is the integrin alphavbeta3, which mediates the migration of activated endothelial cells during vessel formation. MATERIALS AND METHODS: A variety of radiolabelled RGD peptides have been introduced for monitoring of alphavbeta3 expression using nuclear medicine tracer techniques. OBJECTIVES: This review discusses tracer development and highlights some strategies for tracer optimisation. It summarises the preclinical and clinical data and discusses the potential of this class of tracer to characterise angiogenesis.

Animals↗

PubMed2004

Solid-phase synthesis of a small library of 3-phenylthio-3-nicotinyl propionic acid derivatives acting as antagonists of the integrin alphaVbeta3.

We describe the synthesis of a series of low molecular weight inhibitors of the alphavbeta3 integrin obtained by modifying a high-throughput screening hit with micromolar activity. A solid phase synthesis to prepare 3-phenylthio-3-nicotinyl propionic acid derivatives, exemplified by 13c, was set up. Compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit cell adhesion mediated by vitronectin have been obtained.

Cell Adhesion↗

PubMed2006

Effects of a monoclonal anti-alphavbeta3 integrin antibody on blood vessels - a pharmacodynamic study.

PURPOSE: The integrin alphavbeta3 is an adhesion molecule expressed by proliferating endothelial cells and antibodies blocking this integrin inhibit angiogenesis in preclinical models. MEDI-522 is a second generation humanized anti-alphavbeta3 antibody designed for antiangiogenic therapy. The purpose of this study was to examine potential effects of this agent on blood vessels. EXPERIMENTAL DESIGN: In a phase I dose escalation study, MEDI-522 was administered by weekly infusions to 25 adult patients with advanced solid organ malignancies. As a surrogate angiogenesis assay, a wound was created by punch biopsy of the arm skin. This wound site was re-biopsied after a 7-day interval. Dual-label immunofluorescence experiments followed by computer-assisted image analysis were conducted to analyze the vasculature. RESULTS: Sequential pretreatment and 4-week treatment skin biopsy pairs were available on 4 patients, who had received 6 or 10 mg/kg of MEDI-522. MEDI-522 was detected in the dermal blood vessels as well as the dermal interstitium both in intact and wounded skin sites following treatment. No statistically significant difference was found between pretreatment and treatment samples of skin for vascular area, endothelial cell proliferation and apoptosis, or beta3 integrin levels. Phosphorylated focal adhesion kinase (pFAK) was significantly diminished in skin wound vessels during MEDI-522 treatment compared to the pretreatment samples. CONCLUSIONS: MEDI-522 was detectable both in quiescent and in angiogenically active skin blood vessels as well as in the dermal interstitial space. The levels of pFAK were reduced during MEDI-522 treatment, suggesting a modulating effect on this signaling molecule.

Adult↗

PubMed2005

Integrin alphavbeta3 as a target for blocking HIV-1 Tat-induced endothelial cell activation in vitro and angiogenesis in vivo.

OBJECTIVE: The transactivating factor (Tat) of HIV-1 binds to alphavbeta3 integrin present on endothelial cells contributing to neovascularization. Here, we investigated the biological consequences of Tat/alphavbeta3 interaction and the antagonist effect of an Arg-Gly-Asp (RGD)-based peptidomimetic. METHODS AND RESULTS: Binding of Tat to endothelial alphavbeta3 triggers focal adhesion kinase and nuclear factor-kappaB activation, leading to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo. The RGD-peptidomimetic SCH221153 inhibits Tat/alphavbeta3 interaction in a solid phase binding assay and endothelial cell adhesion to immobilized Tat with a potency higher than that of RGD-containing peptides. Accordingly, SCH221153 inhibits Tat/alphavbeta3-dependent focal adhesion kinase and nuclear factor-kappaB activation, proliferation, membrane ruffling, and motility in endothelial cells. Finally, SCH221153 inhibits the angiogenic response triggered by Tat in the chick-embryo chorioallantoic membrane without affecting physiological vascularization. SCH221153 exerts these inhibitory effects without affecting the interaction of Tat with endothelial heparan sulfate proteoglycans or with the vascular endothelial growth factor receptor-2/kinase domain-containing receptor. In all the assays the negative control SCH216687 was ineffective. CONCLUSIONS: These data provide new insights on the mechanism of endothelial cell activation by Tat and point to RGD peptidomimetics as prototypes for the development of novel Tat antagonists.

Animals↗

PubMed1997

Changing ligand specificities of alphavbeta1 and alphavbeta3 integrins by swapping a short diverse sequence of the beta subunit.

Integrins mediate signal transduction through interaction with multiple cellular or extracellular matrix ligands. Integrin alphavbeta3 recognizes fibrinogen, von Willebrand factor, and vitronectin, while alphavbeta1 does not. We studied the mechanisms for defining ligand specificity of these integrins by swapping the highly diverse sequences in the I domain-like structure of the beta1 and beta3 subunits. When the sequence CTSEQNC (residues 187-193) of beta1 is replaced with the corresponding CYDMKTTC sequence of beta3, the ligand specificity of alphavbeta1 is altered. The mutant (alphavbeta1-3-1), like alphavbeta3, recognizes fibrinogen, von Willebrand factor, and vitronectin (a gain-of-function effect). The alphavbeta1-3-1 mutant is recruited to focal contacts on fibrinogen and vitronectin, suggesting that the mutant transduces intracellular signals on adhesion. The reciprocal beta3-1-3 mutation blocks binding of alphavbeta3 to these multiple ligands and to LM609, a function-blocking anti-alphavbeta3 antibody. These results suggest that the highly divergent sequence is a key determinant of integrin ligand specificity. Also, the data support a recent hypothetical model of the I domain of beta, in which the sequence is located in the ligand binding site.

Amino Acid Sequence↗

PubMed2000

Expression of soluble, recombinant alphavbeta3 integrin fragments in Escherichia coli.

No prokaryotic expression of integrin alphavbeta3 has been reported so far. We report here the expression of C-terminally truncated alphavbeta3 receptors in E. coli considering the known features required for dimerization and ligand binding. The expressed protein was insoluble despite of the addition of 'solubilizers' to the culture medium. Osmotic stress conditions combined with added exogenous solutes resulted in a small part of soluble receptor. The alphavbeta3 variants were purified from inclusion bodies or from soluble cytoplasmic maltose binding protein fusions. Heterodimerization of the subunits was proved by immunoprecipitation assays. Receptor-ligand binding was found to depend on the concentration. A competition assay with RGD peptides referred to unspecific receptor-ligand interaction. The latter fact was consistent with the finding that soluble receptors did not bind on RGD peptide-coupled sepharose (GRGDSPK sepharose).

ATP-Binding Cassette Transporters↗

PubMed1996

Osteoclast integrin alphaVbeta3 is present in the clear zone and contributes to cellular polarization.

Osteoclasts are primary bone-resorbing cells with highly polarized cytoplasmic structures, such as ruffled borders and clear zones. In the present study, we have examined the subcellular localization and function of the alphaVbeta3 integrin in primary rat osteoclasts and mouse osteoclast-like multinucleated cells (OCLs) formed in vitro. At the ultrastructural level, the specific immunoreactivity of both alphaV and beta3 subunits is localized not only along the plasma membranes of osteoclast ruffled borders and basolateral membranes but also in clear zones. Addition of GRGDS (Gly-Arg-Gly-Asp-Ser) peptide to the culture medium during a pit formation assay reduces resorbed areas on dentine slices in a dose-dependent manner. Treatment with the GRGDS peptide also dose-dependently inhibits the formation of a ringed structure of F-actin (an "actin ring") in OCLs on dentine slices. Electron-microscopic analysis has revealed that OCLs treated with GRGDS peptide at 1 mM can adhere to dentine slices with unusually broad or poorly defined clear zones but do not form the ruffled burder structure. These results suggest that integrin alphaV and beta3 subunits localized in the ruffled border/clear zone complex of osteoclasts are essential for the functional osteoclast-to-bone matrix interaction and the structural polarization of osteoclasts.

Animals↗

PubMed2004

VP7 mediates the interaction of rotaviruses with integrin alphavbeta3 through a novel integrin-binding site.

Rotavirus entry is a complex multistep process that depends on the trypsin cleavage of the virus spike protein VP4 into polypeptides VP5 and VP8 and on the interaction of these polypeptides and of VP7, the second viral surface protein, with several cell surface molecules, including integrin alphavbeta3. We characterized the effect of the trypsin cleavage of VP4 on the binding to MA104 cells of the sialic acid-dependent virus strain RRV and its sialic acid-independent variant, nar3. We found that, although the trypsin treatment did not affect the attachment of these viruses to the cell surface, their binding was qualitatively different. In contrast to the trypsin-treated viruses, which initially bound to the cell surface through VP4, the non-trypsin-treated variant nar3 bound to the cell through VP7. Amino acid sequence comparison of the surface proteins of rotavirus and hantavirus, both of which interact with integrin alphavbeta3 in an RGD-independent manner, identified a region shared by rotavirus VP7 and hantavirus G1G2 protein in which six of nine amino acids are identical. This region, which is highly conserved among the VP7 proteins of different rotavirus strains, mediates the binding of rotaviruses to integrin alphavbeta3 and probably represents a novel binding motif for this integrin.

Amino Acid Sequence↗

PubMed2005

Pathogenic hantaviruses bind plexin-semaphorin-integrin domains present at the apex of inactive, bent alphavbeta3 integrin conformers.

The alphavbeta3 integrins are linked to human bleeding disorders, and pathogenic hantaviruses regulate the function of alphavbeta3 integrins and cause acute vascular diseases. alphavbeta3 integrins are present in either extended (active) or dramatically bent (inactive) structures, and interconversion of alphavbeta3 conformers dynamically regulates integrin functions. Here, we show that hantaviruses bind human alphavbeta3 integrins and that binding maps to the plexin-semaphorin-integrin (PSI) domain present at the apex of inactive, bent, alphavbeta3-integrin structures. Pathogenic hantaviruses [New York-1 virus (NY-1V) and Hantaan virus (HTNV)] bind immobilized beta3 polypeptides containing the PSI domain, and human (but not murine) beta3 polypeptides inhibit hantavirus infectivity. Substitution of human beta3 residues 1-39 for murine beta3 residues directed pathogenic hantavirus infection of nonpermissive CHO cells expressing chimeric alphavbeta3 receptors. Mutation of murine beta3 Asn-39 to Asp-39 present in human beta3 homologues (N39D) permitted hantavirus infection of cells and specified PSI domain residue interactions with pathogenic hantaviruses. In addition, cell-surface expression of alphavbeta3 locked in an inactive bent conformation conferred hantavirus infectivity of CHO cells. Our findings indicate that hantaviruses bind to a unique domain exposed on inactive integrins and, together with prior findings, suggest that this interaction restricts alphavbeta3 functions that regulate vascular permeability. Our findings suggest mechanisms for viruses to direct hemorrhagic or vascular diseases and provide a distinct target for modulating alphavbeta3-integrin functions.

Amino Acid Sequence↗

PubMedDate not supplied

Radiolabeled multimeric cyclic RGD peptides as integrin alphavbeta3 targeted radiotracers for tumor imaging.

Integrin alphavbeta3 plays a significant role in tumor angiogenesis and is a receptor for the extracellular matrix proteins with the exposed arginine-glycine-aspartic (RGD) tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, lamin, collagen, Von Willibrand's factor, osteoponin, and adenovirus particles. Integrin alphavbeta3 is expressed at low levels on epithelial cells and mature endothelial cells, but it is overexpressed on the activated endothelial cells of tumor neovasculature and some tumor cells. The highly restricted expression of integrin alphavbeta3 during tumor growth, invasion, and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. In the past decade, many radiolabeled linear and cyclic RGD peptide antagonists have been evaluated as the integrin alphavbeta3 targeted radiotracers. Significant progress has been made on their use for imaging tumors of different origin by single photon emission computed tomography (SPECT) or positron emission tomography (PET) in several tumor-bearing animal models. [18F]Galacto-RGD is under clinical investigation as the first integrin alphavbeta3 targeted radiotracer for noninvasive visualization of the activated integrin alphavbeta3 in cancer patients. This review will focus on the radiolabeled multimeric cyclic RGD peptides (dimers and tetramers) useful as radiotracers to image the tumor integrin alphavbeta3 expression by SPECT and PET, and some fundamental aspects for the development of integrin alphavbeta3 targeted radiotracers. These include the choice of radionuclide and bifunctional chelators, selection of targeting biomolecules, and factors influencing the integrin alphavbeta3 binding affinity and tumor uptake, as well as different approaches for modification of radiotracer pharmacokinetics.

Humans↗

PubMed2004

Immunohistochemical localization of alphavbeta3 integrin receptor during experimental tooth movement.

During orthodontic treatment, multinucleated clast cells carry out the resorption of mineralized tissues. Adhesion of clast cells to the mineralized tissues is mediated by transmembrane cell-surface glycoproteins called integrins, specifically by the alphavbeta3 integrin, which plays an important role in the process of bone resorption. The role of the alphavbeta3 integrin in bone resorption leading to osteoporosis has been demonstrated, but its role in alveolar bone and root resorption during orthodontic tooth movement is unknown. This study examined the expression of the alphavbeta3 integrin during experimental tooth movement. Tooth movement was achieved in 16 male Sprague-Dawley rats (each weighing 120-200 g) with elastic bands between their maxillary first and second molars. The molar-bearing segments were dissected and processed for histologic and immunohistochemical examination. The expression of alphavbeta3 integrin was examined with 2 primary antibodies: a polyclonal anti-alphav integrin subunit antibody and a polyclonal anti-beta3 integrin subunit antibody. Negative controls were similarly processed but without incubation with primary antibodies. The alphavbeta3 integrin was expressed both by osteoclasts associated with alveolar bone resorption and by odontoclasts associated with root resorption during experimental tooth movement. Furthermore, the beta3 integrin subunit was expressed by the epithelial rests of Malassez in the periodontal ligament. Negative controls did not show immunolabeling. The alphavbeta3 integrin adhesion receptor is expressed during experimental tooth movement and might be involved in the process of mineralized tissue resorption and the functions of the epithelial rests of Malassez.

Alveolar Process↗

PubMed2005

A novel CYR61-triggered 'CYR61-alphavbeta3 integrin loop' regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway.

The angiogenic inducer CYR61 is differentially overexpressed in breast cancer cells exhibiting high levels of Heregulin (HRG), a growth factor closely associated with a metastatic breast cancer phenotype. Here, we examined whether CYR61, independently of HRG, actively regulates breast cancer cell survival and chemosensitivity, and the pathways involved. Forced expression of CYR61 in HRG-negative MCF-7 cells notably upregulated the expression of its own integrin receptor alphavbeta3 (>200 times). Small peptidomimetic alphavbeta3 integrin antagonists dramatically decreased cell viability of CYR61-overexpressing MCF-7 cells, whereas control MCF-7/V remained insensitive. Mechanistically, functional blockade of alphavbeta3 specifically abolished CYR6-induced hyperactivation of ERK1/ERK2 MAPK, whereas the activation status of AKT did not decrease. Moreover, CYR61 overexpression rendered MCF-7 cells significantly resistant (>10-fold) to Taxol-induced cytotoxicity. Remarkably, alphavbeta3 inhibition converted the CYR61-induced Taxol-resistant phenotype into a hypersensitive one. Thus, the augmentation of Taxol-induced apoptotic cell death in the presence of alphavbeta3 antagonists demonstrated a strong synergism as verified by the terminal transferase-mediated dUTP nick-end labeling (TUNEL) assay and by flow cytometric analysis for DNA content. Indeed, functional blockade of alphavbeta3, similarly to the pharmacological MAPK inhibitor U0126, synergistically increased both the proportion of CYR61-overexpressing breast cancer cells in the G2 phase of the cell cycle and the appearance of sub-G1 hypodiploid (apoptotic) cells caused by Taxol. Strikingly, CYR61 overexpression impaired the accumulation of wild-type p53 following Taxol exposure, while inhibition of alphavbeta3 or ERK1/ERK2 MAPK signalings completely restored Taxol-induced upregulation of p53. Moreover, antisense downregulation of CYR61 expression abolished the anchorage-independent growth of breast cancer cells engineered to overexpress HRG, and significantly increased their sensitivity to Taxol. Our data provide evidence that CYR61 is sufficient to promote breast cancer cell proliferation, cell survival, and Taxol resistance through a alphavbeta3-activated ERK1/ERK2 MAPK signaling. The identification of a 'CYR61-alphavbeta3 autocrine loop' in the epithelial compartment of breast carcinoma strongly suggests that targeting alphavbeta3 may simultaneously prevent breast cancer angiogenesis, growth, and chemoresistance.

Angiogenesis Inducing Agents↗

PubMed2004

c-Src-dependent cross-talk between CEACAM6 and alphavbeta3 integrin enhances pancreatic adenocarcinoma cell adhesion to extracellular matrix components.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an immunoglobulin superfamily member with a diversity of extracellular ligands that is implicated in the initiation and progression of a variety of malignancies. We sought to characterize the effects of CEACAM6 crosslinking on pancreatic adenocarcinoma cellular interaction with the extracellular matrix (ECM) components fibronectin and vitronectin. Antibody-mediated CEACAM6 crosslinking was performed and the ability of BxPC3 cells, which inherently overexpress CEACAM6, to adhere to fibronectin and vitronectin was quantified. The roles of the archetypal fibronectin (alpha5beta1 integrin) and vitronectin (alphavbeta3 integrin) receptors were determined. The effects of c-Src inhibition were investigated using the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) and c-Src specific RNA interference. CEACAM6 crosslinking initiates c-Src-dependent cross-talk between CEACAM6 and alphavbeta3 integrin, leading to increased ECM component adhesion. CEACAM6-mediated signaling events may contribute to the invasive and metastatic potential of pancreatic adenocarcinoma cells by promoting their interaction with ECM components.

Adenocarcinoma↗

PubMed2006

Integrin alpha3beta1, a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant Inhibitor for integrin alphavbeta3.

Exogenous soluble human alpha3 noncollagenous (NC1) domain of collagen IV inhibits angiogenesis and tumor growth. These biological functions are attributed to the binding of alpha3NC1 to integrin alphavbeta3. However, in some tumor cells that express integrin alphavbeta3, the alpha3NC1 domain does not inhibit proliferation, suggesting that integrin alphavbeta3 expression is not sufficient to mediate the anti-tumorigenic activity of this domain. Therefore, in the present study, we searched for novel binding receptors for the soluble alpha3NC1 domain in cells lacking alphavbeta3 integrin. In these cells, soluble alpha3NC1 bound integrin alpha3beta1; however, unlike alphavbeta3, alpha3beta1 integrin did not mediate cell adhesion to immobilized alpha3NC1 domain. Interestingly, in cells lacking integrin alpha3beta1, adhesion to the alpha3NC1 domain was enhanced due to activation of integrin alphavbeta3. These findings indicate that integrin alpha3beta1 is a receptor for the alpha3NC1 domain and transdominantly inhibits integrin alphavbeta3 activation. Thus integrin alpha3beta1, in conjunction with integrin alphavbeta3, modulates cellular responses to the alpha3NC1 domain, which may be pivotal in the mechanism underpinning its anti-angiogenic and anti-tumorigenic activities.

Cell Adhesion↗

PubMed2002

Expression of integrin alphaVbeta3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis.

INTRODUCTION: Overexpression of integrin alphaVbeta3 had been demonstrated in various tumors. Studies have suggested that elevated levels of integrin alphaVbeta3 in melanoma cells are deeply involved in the mechanism of increased melanoma invasiveness. AIMS: To examine the expression of integrin alphaVbeta3 in pancreatic carcinoma and to evaluate the correlation between integrin expression accompanied by MMP-2 activation and clinicopathologic factors. METHODOLOGY: Integrin alphaVbeta3 specific antibody LM-609 was used for immunochemical analysis, and intracellular localization was determined in human pancreatic cancer cell lines cultured on vitronectin coating. Fifty pancreatic adenocarcinomas analyzed immunohistochemically and 26 frozen samples were analyzed gelatin-zymographically. RESULTS: Two of three pancreatic cancer cell lines demonstrated integrin alphaVbeta3 immunofluorescence with a membranous pattern, and 29 of 50 pancreatic carcinomas showed positive immunostaining of tumor cells. There was no significant correlation between integrin alphaVbeta3 expression and tumor size, tumor grade, or peripancreatic invasion. However, primary tumors with lymph node metastasis featured significantly higher expression of integrin alphaVbeta3 than those without node metastasis. Tumors with high integrin alphaVbeta3 expression showed significantly higher MMP-2 activation ratios than did tumors with low expression. CONCLUSION: Expression analysis in pancreatic cancer tissue demonstrated involvement of alphaVbeta3 integrin in lymph node metastasis rather than peripancreatic invasion. MMP-2 activation is linked, at least in part, to the expression of integrin alphaVbeta3 of pancreatic cancer cells.

Aged↗

PubMed2005

Targeted inhibition of alphavbeta3 integrin with an RNA aptamer impairs endothelial cell growth and survival.

Alphavbeta3 integrin is a crucial factor involved in a variety of physiological processes, such as cell growth and migration, tumor invasion and metastasis, angiogenesis, and wound healing. Alphavbeta3 integrin exerts its effect by regulating endothelial cell (EC) migration, proliferation, and survival. Inhibiting the function of alphavbeta3 integrin, therefore, represents a potential anti-cancer, anti-thrombotic, and anti-inflammatory strategy. In this study, we tested an RNA aptamer, Apt-alphavbeta3 that binds recombinant alphavbeta3 integrin, for its ability to bind endogenous alphavbeta3 integrin on the surface of cells in culture and to subsequently affect cellular response. Our data illustrate that Apt-alphavbeta3 binds alphavbeta3 integrin expressed on the surface of live HUVECs. This interaction significantly decreases both basal and PDGF-induced cell proliferation as well as inhibition of cell adhesion. Apt-alphavbeta3 can also reduce PDGF-stimulated tube formation and increase HUVEC apoptosis through inhibition of FAK phosphorylation pathway. Our results demonstrate that by binding to its target, Apt-alphavbeta3 can efficiently inhibit human EC proliferation and survival, resulting in reduced angiogenesis. It predicts that Apt-alphavbeta3 could become useful in both tumor imaging and the treatment of tumor growth, atherosclerosis, thrombosis, and inflammation.

Aptamers, Nucleotide↗

PubMed2005

Quantifying the specific binding between West Nile virus envelope domain III protein and the cellular receptor alphaVbeta3 integrin.

A previous study has illustrated that the alphaVbeta3 integrin served as the functional receptor for West Nile virus (WNV) entry into cells. Domain III (DIII) of WNV envelope protein (E) was postulated to mediate virus binding to the cellular receptor. In this study, the specificity and affinity binding of WNV E DIII protein to alphaVbeta3 integrin was confirmed with co-immunoprecipitation and receptor competition assay. Binding of WNV E DIII protein to alphaVbeta3 integrin induced the phosphorylation of focal adhesion kinase that is required to mediate ligand-receptor internalization into cells. A novel platform was then developed using the atomic force microscopy to measure this specific binding force between WNV E DIII protein and the cellular receptor, alphaVbeta3 integrin. The single protein pair-interacting force measured was in the range of 45 +/- 5 piconewtons. This interacting force was highly specific as minimal force was measured in the WNV E DIII protein interaction with alphaVbeta5 integrin molecules and heparan sulfate. These experiments provided an insight to quantitate virus-receptor interaction. Force measurement using atomic force microscopy can serve to quantitatively analyze the effect of candidate drugs that modulate virus-host receptor affinity.

Cell Line, Tumor↗

PubMed2006

Discovery of small molecule inhibitors of integrin alphavbeta3 through structure-based virtual screening.

Inhibitors of integrin alphavbeta3 have been implicated in the treatment of a variety of diseases, including tumor metastasis, neovascularization, osteoporosis, and rheumatoid arthritis. It is therefore desirable to develop new types of small molecule inhibitors of integrin alphavbeta3. Here we describe the discovery of novel classes of small molecule inhibitors, via structure-based virtual screening, that target the ligand binding site of integrin alphavbeta3. Application of the docking procedure for screening of a commercially available compound database resulted in a 1774-fold reduction in the size of the screening set (88695 to 50 compounds) and gave a hit-rate of 14% upon biological evaluation (IC50 value ranging from 30 to 200 microM). The best hit, compound 37, 3,4-dichloro-phenylbiguanide, showed inhibitory activity, in a time- and dose-dependent manner, in both cell motility and angiogenesis assays. Based on the best hit, compound 37, a more effective derivative compound 62 has been identified. Furthermore, molecular graphics analyses of a series of substituted phenylbiguanides were carried out to predict the binding mode between the active compounds and integrin alphavbeta3. Our results indicate that the substituted phenylbiguanides might be involved in the inhibition of bivalent cation-mediated ligand binding of integrin alphavbeta3.

Biguanides↗