Abstract
Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; α4β1; CD49d / CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-inflammatory drugs for the treatment of asthma. Here, we review our efforts to use rational design to identify potent, selective inhibitors of VLA-4. We describe the discovery of a series of potent VLA-4 inhibitors through the addition of a novel N-terminal organic cap to a tetrapeptide VLA-4 binding motif 4-((N-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro ; Kd = 70 pM), and rationalize their structure-activity relationships using 3D-QSAR. Also, we show our rational peptidomimetic design strategy using “template hopping” from the gpIIb / IIIa integrin antagonist field, and also a novel virtual screening strategy. Two series have been developed, one that has high selectivity for the activated over the non-activated state of the receptor, and the other which is non-selective inhibiting both activated and non-activated VLA-4. Both series are highly selective for VLA-4 versus against other integrin family members. These inhibitors show promise in the treatment of asthma, based upon efficacy in a sheep model of asthma, where they inhibit both the early and late-phase responses to asthma and also block hypersensitivity.
Keywords: integrins, chronic inflammatory disease, asthma, peptide library
Current Topics in Medicinal Chemistry
Title: Rational Design of Potent and Selective VLA-4 Inhibitors and their Utility in the Treatment of Asthma
Volume: 4 Issue: 14
Author(s): Juswinder Singh, Steve Adams, Mary Beth Carter, Hernan Cuervo, Wen-Cherng Lee, Roy R. Lobb, R. Blake Pepinsky, Russell Petter and Daniel Scott
Affiliation:
Keywords: integrins, chronic inflammatory disease, asthma, peptide library
Abstract: Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; α4β1; CD49d / CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-inflammatory drugs for the treatment of asthma. Here, we review our efforts to use rational design to identify potent, selective inhibitors of VLA-4. We describe the discovery of a series of potent VLA-4 inhibitors through the addition of a novel N-terminal organic cap to a tetrapeptide VLA-4 binding motif 4-((N-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro ; Kd = 70 pM), and rationalize their structure-activity relationships using 3D-QSAR. Also, we show our rational peptidomimetic design strategy using “template hopping” from the gpIIb / IIIa integrin antagonist field, and also a novel virtual screening strategy. Two series have been developed, one that has high selectivity for the activated over the non-activated state of the receptor, and the other which is non-selective inhibiting both activated and non-activated VLA-4. Both series are highly selective for VLA-4 versus against other integrin family members. These inhibitors show promise in the treatment of asthma, based upon efficacy in a sheep model of asthma, where they inhibit both the early and late-phase responses to asthma and also block hypersensitivity.
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Cite this article as:
Singh Juswinder, Adams Steve, Carter Beth Mary, Cuervo Hernan, Lee Wen-Cherng, Lobb R. Roy, Pepinsky Blake R., Petter Russell and Scott Daniel, Rational Design of Potent and Selective VLA-4 Inhibitors and their Utility in the Treatment of Asthma, Current Topics in Medicinal Chemistry 2004; 4 (14) . https://dx.doi.org/10.2174/1568026043387520
DOI https://dx.doi.org/10.2174/1568026043387520 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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