αvβ3‐ oder α5β1‐Integrin‐selektive Peptidmimetika für die Oberflächenbeschichtung

Mas‐Moruno, Carlos; Fraioli, Roberta; Rechenmacher, Florian; Neubauer, Stefanie; Kapp, Tobias G.; Kessler, Horst

doi:10.1002/ange.201509782

Cited by 15 publications

(3 citation statements)

References 211 publications

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“…Since the early 1990s, Kessler and his group developed cyclic pentapeptides ( Aumailley et al, 1991 ; Gurrath et al, 1992 ; Haubner et al, 1997 ) first with a high affinity for the integrin α V β 3 but a low selectivity against integrin α 5 β 1 , which is also a RGD recognizing integrin ( Schaffner et al, 2013 ). Later, iso DGR peptides ( Frank et al, 2010 ; Bochen et al, 2013 ; Mas-Moruno et al, 2016a ) and linear tyrosine-based RGD mimetics were investigated ( Heckmann et al, 2007 ; Heckmann et al, 2009 ). The group of DeGrado designed and synthesized linear RGD mimetics with high affinity and high selectivity against integrin α 5 β 1 based on a diamine scaffold ( Corbett et al, 1997 ; Rockwell et al, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of a Non-Peptide Small-Molecule Drug Conjugate Targeting Integrin αVβ3

Paulus

Sewald

2022

Front. Chem.

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An integrin αVβ3-targeting linear RGD mimetic containing a small-molecule drug conjugate (SMDC) was synthesized by combining the antimitotic agent monomethyl auristatin E (MMAE), an enzymatically cleavable Val-Ala-PABC linker with a linear conjugable RGD mimetic. The structure proposal for the conjugable RGD mimetic was suggested upon the DAD mapping analysis of a previously synthesized small-molecule RGD mimetic array based on a tyrosine scaffold. Therefore, a diversifying strategy was developed as well as a novel method for the partial hydrogenation of pyrimidines in the presence of the hydrogenolytically cleavable Cbz group. The small-molecule RGD mimetics were evaluated in an ELISA-like assay, and the structural relationships were analyzed by DAD mapping revealing activity differences induced by structural changes as visualized in dependence on special structural motifs. This provided a lead structure for generation of an SMDC containing the antimitotic drug MMAE. The resulting SMDC containing a linear RGD mimetic was tested in a cell adhesion and an in vitro cell viability assay in comparison to reference SMDCs containing cRGDfK or cRADfK as the homing device. The linear RGD SMDC and the cRGDfK SMDC inhibited adhesion of αVβ3-positive WM115 cells to vitronectin with IC50 values in the low µM range, while no effect was observed for the αVβ3-negative M21-L cell line. The cRADfK SMDC used as a negative control was about 30-fold less active in the cell adhesion assay than the cRGDfK SMDC. Conversely, both the linear RGD SMDC and the cRGDfK SMDC are about 55-fold less cytotoxic than MMAE against the αVβ3-positive WM115 cell line with IC50 values in the nM range, while the cRADfK SMDC is 150-fold less cytotoxic than MMAE. Hence, integrin binding also influences the antiproliferative activity giving a targeting index of 2.8.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of a Non-Peptide Small-Molecule Drug Conjugate Targeting Integrin αVβ3

Paulus

Sewald

2022

Front. Chem.

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“…Hence, we conjugated a Pd 2 L 4 metallacage to four integrin ligands for subtype specific targeting of integrin αvβ3 (compounds 1 – 3 ) ,, or α5β1 (compound 4 ), respectively (Figure ). ,,, Cage formation and cisplatin encapsulation were studied by NMR spectroscopy. The conjugated cages were first studied for their integrin recognition properties using an ELISA assay.…”

Section: Introductionmentioning

confidence: 99%

Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

et al. 2018

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Cisplatin occupies a crucial role in the treatment of various malignant tumours. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity. Thus, Pd2L4 cages (L = ligand) have been conjugated to four integrin ligands with different binding affinity and selectivity. Cage formation and encapsulation of cisplatin was proven by NMR spectroscopy. Upon encapsulation, cisplatin showed increased cytotoxicity in vitro, in melanoma A375 cells overexpressing αvβ3 integrins. Moreover, ex vivo studies in tissue slices indicated reduced toxicity towards healthy liver and kidney tissues for cage-encapsulated cisplatin. Analysis of metal content by ICP-MS demonstrated that encapsulated drug is less accumulated in these organs compared to the 'free' one.

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“…Receptors for a variety of integrins, such as αvβ3 and α5β1, are highly expressed on the surface of activated HSCs [50] . Therefore, nanomaterials that target integrin receptors have been extensively studied.…”

Section: Nanomaterials Modified With Liver‐targeting Peptidesmentioning

confidence: 99%

Peptide‐Based Nanoarchitectonics for the Treatment of Liver Fibrosis

Huang

Zou

2023

ChemBioChem

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Liver fibrosis is a process of excessive accumulation of extracellular matrix caused by liver injury. Liver fibrosis can progress to cirrhosis or even liver cancer without proper intervention. Until now, no effective therapeutic drugs have been clinically approved for treating liver fibrosis. Hence, the development of safe and effective antifibrotic drugs is particularly important. As a representative biomaterial, peptides have been investigated as key components for constructing antifibrotic nanomaterials given their advantages of biological origination, synthetic availability, and good biocompatibility. Peptides serve as multifunctional motifs in antifibrotic nanomaterials, such as liver‐targeting molecules, antifibrotic molecules, and self‐assembling building blocks for the formation of the nanomaterials. In this review, we focus on peptide‐based nanoarchitectonics for treating liver fibrosis, including nanomaterials modified with liver‐targeting peptides, nanomaterials for the efficient delivery of antifibrotic peptides, and self‐assembled peptide nanomaterials for the delivery of antifibrotic drugs. The design rules of these peptide‐based nanomaterials are described. The antifibrotic mechanisms and effects of these peptide‐based nanomaterials in treating liver fibrosis and related diseases are highlighted. The challenges and future perspectives of using peptide‐based nanoarchitectonics for the treatment of liver fibrosis are discussed. These results are expected to accelerate the rational design and clinical translation of antifibrotic nanomaterials.

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αvβ3‐ oder α5β1‐Integrin‐selektive Peptidmimetika für die Oberflächenbeschichtung

Cited by 15 publications

References 211 publications

Synthesis and Evaluation of a Non-Peptide Small-Molecule Drug Conjugate Targeting Integrin αVβ3

Synthesis and Evaluation of a Non-Peptide Small-Molecule Drug Conjugate Targeting Integrin αVβ3

Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

Peptide‐Based Nanoarchitectonics for the Treatment of Liver Fibrosis

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