R-Isomers of Arg-Gly-Asp (RGD) mimics as potent αvβ3 inhibitors

Nagarajan, Srinivasan; Devadas, Balekudru; Malecha, James W.; Lu, Hwang‐Fun; Ruminski, Peter; Rico, Joseph G.; Rogers, Thomas E.; Marrufo, Laura D.; Collins, Joe; Kleine, H.; Lantz, Melissa K.; Zhu, Jing; Green, Nawasa F.; Russell, Mark A.; Landis, Bryan H.; Miller, Larry; Meyer, Debra M.; Duffin, Tiffany; Engleman, V. Wayne; Finn, Mary Beth; Freeman, Sandra K.; Griggs, David W.; Williams, Melanie; Nickols, Maureen A.; Pegg, Jodi A.; Shannon, Kristen E.; Steininger, Christina N.; Westlin, Marisa M.; Nickols, G. Allen; Keene, Jeffery L.

doi:10.1016/j.bmc.2007.03.034

Cited by 16 publications

(8 citation statements)

References 25 publications

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“…The effects of CWHM 12 and CWHM 96 on cell adhesion mediated by αvβ3, αvβ5, αvβ6, and α5β1 were measured as previously described with minor modifications 50,51 . Briefly, stably transfected human 293 cells over-expressing human αvβ3 or αvβ5 were pre-incubated in HBSS buffer (Sigma) containing 200 μM MnCl 2 for 30 min at 37 °C with 3-fold dilutions of compound.…”

Section: Methodsmentioning

confidence: 99%

Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs

Henderson

Arnold

Katamura

et al. 2013

Nat Med

719

678

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Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb-Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl4-induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

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Section: Methodsmentioning

confidence: 99%

Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs

Henderson

Arnold

Katamura

et al. 2013

Nat Med

719

678

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“…Independent of the direct biochemical role in TGF‐β activation, RGD‐binding integrins are important mechanosensors and transducers that provide cells such as myofibroblasts and their precursors’ information regarding the components and stiffness of their local ECM (Fiore et al, ; Lampi & Reinhart‐King, ; Santos & Lagares, ). There is evidence that fibrotic ECM adapts cells to a pro‐fibrotic phenotype rather than vice versa (Nagarajan et al, ). Furthermore, the RGD‐containing protein fibronectin, which is bound and assembled by integrin α5β1, is robustly deposited in remodeling tissue and is essential to collagen matrix deposition and maintenance (Zollinger & Smith, ).…”

Section: Discussionmentioning

confidence: 99%

“…Potency for the compounds in blocking cell attachment mediated by integrins αvβ3, αvβ5, and αvβ6 was measured as previously described (Henderson et al, ). Potency for blocking cell attachment mediated by integrins αvβ1, αvβ8, and α8β1 was measured using modifications of this method which are briefly summarized as follows: To assess CWHM‐12 and CWHM‐680 effects on cellular αvβ1 function, we varied its concentration in an assay measuring binding of HEK‐293 cells, which naturally express this integrin (Nagarajan et al, ), to the surface of 96‐well plates coated with purified recombinant human TGFβ‐1 latency‐associated peptide (R&D Systems). To assess the effect on cellular αvβ8 function, we performed the assay with the same LAP ligand but with HEK‐293 cells which had been stably transfected to overexpress this integrin.…”

Section: Methodsmentioning

confidence: 99%

Pharmacologic inhibition of RGD‐binding integrins ameliorates fibrosis and improves function following kidney injury

et al. 2020

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Fibrosis is a final common pathway for many causes of progressive chronic kidney disease (CKD). Arginine-glycine-aspartic acid (RGD)-binding integrins are important mediators of the pro-fibrotic response by activating latent TGF-β at sites of injury and by providing myofibroblasts information about the composition and stiffness of the extracellular matrix. Therefore, blockade of RGD-binding integrins may have therapeutic potential for CKD. To test this idea, we used small-molecule peptidomimetics that potently inhibit a subset of RGD-binding integrins in a murine model of kidney fibrosis. Acute kidney injury leading to fibrosis was induced by administration of aristolochic acid. Continuous subcutaneous administration of CWHM-12, an RGD integrin antagonist, for 28 days improved kidney function as measured by serum creatinine. CWHM-12 significantly reduced Collagen 1 (Col1a1) mRNA expression and scar collagen deposition in the kidney. Protein and gene expression markers of activated myofibroblasts, a major source of extracellular matrix deposition in kidney fibrosis, were diminished by treatment. RNA sequencing revealed that inhibition of RGD integrins influenced multiple pathways that determine the outcome of the response to injury and of repair processes. A second RGD integrin antagonist, CWHM-680, administered once daily by oral gavage was also effective in ameliorating fibrosis. We conclude that targeting RGD integrins with such smallmolecule antagonists is a promising therapeutic approach in fibrotic kidney disease.

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“…Derivatives of (R)-3amino-3-(3,5 dichlorophenyl) propanoic acid and (S)-3-amino- 3-(3-pyridyl) propanoic acid have experienced as integrin receptor antagonists [44,45]. Elarofiban (RWJ-53308) is a fibrinogen receptor antagonist along with an antithrombotic effect [46]. It holds an (S)-3-amino-3-(3-pyridyl) propanoic acid subunit.…”

Section: Vitronectin Receptormentioning

confidence: 99%

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

Riaz¹,

Fazal-ur-Rehman²,

Ahmad³

2017

Med chem

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Abstractβ-amino acids are an important class of macromolecules. They play role in life for survival. β-amino acids gained significant interest due to their interesting pharmaceutical uses as hypoglycemic, antiketogenic characteristics, sterile and antifungal activities, anthelminthic as well as potent insecticidal characteristics. These are vital building blocks for the preparation of pharmaceutical and agrochemical target molecules. These are utilized in development of drugs, bimolecular structure and molecular recognition. They are also important in treatment of different diseases which are viral to human health. They play important role in regulation of nutritional metabolism and immunity. It has also led to their wider adoption as intermediates in new drugs and has been a focus of considerable attention in medicinal chemistry. β-amino acids have found extensive applications as components of biologically active peptides and small molecule pharmaceuticals. Synthetic derivatives of biologically relevant peptides incorporating β-amino acids often display interesting pharmacological activity, with increased potency and enzymatic stability. β-peptides participate in arrangement of incredible stable auxiliary structures. This review summarizes recent developments about the different roles of β-amino acids in human biology and some implications in medicinal chemistry.

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R-Isomers of Arg-Gly-Asp (RGD) mimics as potent αvβ3 inhibitors

Cited by 16 publications

References 25 publications

Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs

Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs

Pharmacologic inhibition of RGD‐binding integrins ameliorates fibrosis and improves function following kidney injury

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

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