التفاصيل البيبلوغرافية
| العنوان: |
Improved Lymphocyte Function-associated Antigen-1 (LFA-1) Inhibition by Statin Derivatives. |
| المؤلفون: |
Weitz-Schmidt, Gabriele1 gabriele.weitz@pharma.novartis.com, Welzenbach, Karl1, Dawson, Janet1, Kallen, Joerg1 joerg.kallen@pharma.novartis.com |
| المصدر: |
Journal of Biological Chemistry. 11/5/2004, Vol. 279 Issue 45, p46764-46771. 8p. 2 Diagrams, 3 Charts, 10 Graphs. |
| مصطلحات موضوعية: |
*STATINS (Cardiovascular agents), *LYMPHOCYTES, *T cells, *ISOPENTENOIDS, *ANTICHOLESTEREMIC agents, *ANTIGENS |
| مستخلص: |
The integrin lymphocyte function-associated antigen-1 (LFA-1) (αLβ2; CD11a/CD18) plays an important role in leukocyte migration and T cell activation. LFA-1 is inhibited by the cholesterol-lowering drug lovastatin, which binds to an allosteric site of the αL I domain termed the lovastatin site (L-site). Here we report for the first time the x-ray structures of the LFA-1 I domain complexed with derivatives of lovastatin optimized for LFA-1 inhibition. This analysis identified two new subpockets within the L-site occupied by chemical groups of the statin derivatives but not by lovastatin itself. Occupancy of these L-site subpockets led to distinct conformational changes in LFA-1, which were detectable by an epitope-monitoring assay. We utilized this assay to demonstrate improved LFA-1 inhibition in human blood in vitro and in blood samples from treated animals ex vivo. Moreover, we demonstrate that the novel lovastatin-derived LFA-1 inhibitor LFA878 exhibits potent anti-inflammatory effects in carrageenan-induced rat paw edema. In summary, the findings reported here extend the understanding of LFA-1 inhibition at the molecular level, allow for the identification and design of LFA-1 inhibitors of further enhanced potency, and support the expectation that LFA-1 inhibitors binding to the L-site will be of therapeutic value in treating inflammatory diseases. [ABSTRACT FROM AUTHOR] |
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