New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8ß1 and α11ß1, Induced Specifically on Activated Stellate Cells.
Int J Mol Sci
; 22(23)2021 Nov 26.
Article
em En
| MEDLINE
| ID: mdl-34884600
ABSTRACT
A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvß1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFß activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, "disease specificity" has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner αIIbß3 on platelets, α4ß1, α4ß7 and αLß2 on leukocytes. Herein, "disease specific" integrins would serve as attractive targets. α8ß1 and α11ß1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather "pathology specific" nature of these new integrins. The monoclonal antibodies against α8ß1 and α11ß1 in preclinical examinations may illuminate the road to the first medical agents.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Integrinas
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Receptores de Colágeno
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Células Estreladas do Fígado
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Cirrose Hepática
Limite:
Animals
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Humans
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão