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      Novel Ligands Targeting α 4β 1 Integrin: Therapeutic Applications and Perspectives

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          Abstract

          Among the other members of the adhesion molecules' family, α 4β 1 integrin, a heterodimeric receptor, plays a crucial role in inflammatory diseases, cancer development, metastasis and stem cell mobilization or retention. In many cases, its function in pathogenesis is not yet completely understood and investigations on ligand binding and related stabilization of active/inactive conformations still represent an important goal. For this reason, starting from the highlight of α 4β 1 functions in human pathologies, we report an overview of synthetic α 4β 1 integrin ligands under development as potential therapeutic agents. The small molecule library that we have selected represents a collection of lead compounds. These molecules are the object of future refinement in academic and industrial research, in order to achieve a fine tuning of α 4β 1 integrin regulation for the development of novel agents against pathologies still eluding an effective solution.

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          Most cited references78

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          Integrin ligands at a glance.

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            Origins of metastatic traits.

            How cancer cells acquire the competence to colonize distant organs remains a central question in cancer biology. Tumors can release large numbers of cancer cells into the circulation, but only a small proportion of these cells survive on infiltrating distant organs and even fewer form clinically meaningful metastases. During the past decade, many predictive gene signatures and specific mediators of metastasis have been identified, yet how cancer cells acquire these traits has remained obscure. Recent experimental work and high-resolution sequencing of human tissues have started to reveal the molecular and tumor evolutionary principles that underlie the emergence of metastatic traits. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Integrin-based therapeutics: biological basis, clinical use and new drugs

              Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.
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                Author and article information

                Contributors
                Journal
                Front Chem
                Front Chem
                Front. Chem.
                Frontiers in Chemistry
                Frontiers Media S.A.
                2296-2646
                09 July 2019
                2019
                : 7
                : 489
                Affiliations
                [1] 1Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
                [2] 2Department of Chemistry “G. Ciamician,” University of Bologna , Bologna, Italy
                Author notes

                Edited by: Simona Rapposelli, University of Pisa, Italy

                Reviewed by: Benjamin Sredni, Bar-Ilan University, Israel; Salvatore Di Maro, Second University of Naples, Italy

                *Correspondence: Santi Spampinato santi.spampinato@ 123456unibo.it

                This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of the journal Frontiers in Chemistry

                Article
                10.3389/fchem.2019.00489
                6629825
                31338363
                4713210f-bf52-40b6-acc8-467f6f793c87
                Copyright © 2019 Baiula, Spampinato, Gentilucci and Tolomelli.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 May 2019
                : 25 June 2019
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 88, Pages: 12, Words: 7141
                Categories
                Chemistry
                Mini Review

                α4β1 integrin,agonist,antagonist,small molecules,inflammatory disorders

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