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Targeting integrin αvβ3 by a rationally designed protein for chronic liver disease treatment.

ABSTRACT: Chronic Liver Diseases (CLD) are characterized by abnormal accumulation of collagen fibrils, neo-angiogenesis, and sinusoidal remodeling. Collagen deposition along with intrahepatic angiogenesis and sinusoidal remodeling alters sinusoid structure resulting in portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for CLDs. However, the success of such treatments is limited and unpredictable. We report a strategy for CLD treatment by induction of integrin α_vβ₃ mediated cell apoptosis using a rationally designed protein (ProAgio). ProAgio is designed to target integrin α_vβ₃ at a novel site. Integrin α_vβ₃ is highly expressed in activated Hepatic Stellate Cells (HSC), angiogenic endothelium, and capillarized Liver Sinusoidal Endothelial Cells (LSEC). ProAgio induces apoptosis of these disease causative cells. Tests with liver fibrosis mouse models demonstrate that ProAgio reverses liver fibrosis and relieves blood flow resistance by depleting activated HSC and capillarized LSEC. Our studies demonstrate an effective approach for CLD treatment.

SUBMITTER: Turaga RC

PROVIDER: S-EPMC8445973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Heterobivalent agents targeting PSMA and integrin-αvβ3.

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| S-EPMC4112557 | biostudies-literature

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| S-EPMC2635054 | biostudies-literature

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| S-EPMC3847293 | biostudies-literature

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Project description:At present there are no drugs for the treatment of chronic liver fibrosis that have been approved by the Food and Drug administration of the United States. Telmisartan, a small-molecule antihypertensive drug, displays antifibrotic activity, but its clinical use is limited because it causes systemic hypotension. Here, we report the scalable and convergent synthesis of macromolecular telmisartan prodrugs optimized for preferential release in diseased liver tissue. We optimized the release of active telmisartan in fibrotic liver to be depot-like (that is, a constant therapeutic concentration) through the molecular design of telmisartan brush-arm star polymers, and show that these lead to improved efficacy and to the avoidance of dose-limiting hypotension in both metabolically and chemically induced mouse models of hepatic fibrosis, as determined by histopathology, enzyme levels in the liver, intact-tissue protein markers, hepatocyte necrosis protection, and gene-expression analyses. In rats and dogs, the prodrugs are retained long-term in liver tissue and have a well-tolerated safety profile. Our findings support the further development of telmisartan prodrugs that enable infrequent dosing in the treatment of liver fibrosis.

| S-EPMC6433387 | biostudies-literature

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Project description: Not available

| S-EPMC2728599 | biostudies-literature

Therapeutic targeting of GCB- and ABC-DLBCL by rationally designed BCL6 inhibitor

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2016-10-12 | GSE80351 | GEO

Therapeutic targeting of GCB- and ABC-DLBCLs by rationally designed BCL6 inhibitors

Project description:BCL6 inhibitor induces derepression of BCL6 target genes and shows a similar transcriptional program to BCL6 siRNA

2016-10-13 | GSE79888 | GEO

Rationally designed treatment for metastatic colorectal cancer: current drug development strategies.

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