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Rational Design of Potent and Selective VLA-4 Inhibitors and their Utility in the Treatment of Asthma

[ Vol. 4 , Issue. 14 ]


Juswinder Singh, Steve Adams, Mary Beth Carter, Hernan Cuervo, Wen-Cherng Lee, Roy R. Lobb, R. Blake Pepinsky, Russell Petter and Daniel Scott   Pages 1497 - 1507 ( 11 )


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.


integrins, chronic inflammatory disease, asthma, peptide library


12 Cambridge Center,Cambridge, MA 02142, USA.

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