Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness.

Inhibition of integrin α5β1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5β1 by backbone replacement of known αvβ1 integrin inhibitors. These integrin α5β1 inhibitors also retain the nanomolar potency against αvβ1 integrin, which shows promise for developing dual integrin α5β1/αvβ1 inhibitor.

A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion.

Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor β (TGFβ)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma.

Pharmacologic Blockade of v1 Integrin Ameliorates Renal Failure and Fibrosis .

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells is poorly understood. PDGF receptor (PDGFR) is highly expressed in activated pericytes, a main source of fibroblasts.

Transforming growth factor-β plays divergent roles in modulating vascular remodeling, inflammation, and pulmonary fibrosis in a murine model of scleroderma.

The efficacy and feasibility of targeting transforming growth factor-β (TGFβ) in pulmonary fibrosis and lung vascular remodeling in systemic sclerosis (SSc) have not been well elucidated. In this study we analyzed how blocking TGFβ signaling affects pulmonary abnormalities in Fos-related antigen 2 (Fra-2) transgenic (Tg) mice, a murine model that manifests three important lung pathological features of SSc: fibrosis, inflammation, and vascular remodeling. To interrupt TGFβ signaling in the Fra-2 Tg mice, we used a pan-TGFβ-blocking antibody, 1D11, and Tg mice in which TGFβ receptor type 2 (Tgfbr2) is deleted from smooth muscle cells and myofibroblasts (α-SMA-Cre;Tgfbr2).

Exploring -Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors.

One small molecule inhibitor of αvβ1 integrin, , shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized analogues and systematically investigate their structure-activity relationships (SAR) in αvβ1 integrin inhibition. -Phenylsulfonyl-l-homoproline analogues of maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins.