Improved lymphocyte function-associated antigen-1 (LFA-1) inhibition by statin derivatives: molecular basis determined by x-ray analysis and monitoring of LFA-1 conformational changes in vitro and ex vivo.

Abstract

The integrin lymphocyte function-associated antigen-1 (LFA-1) (alphaLbeta2; 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 alphaL 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.

• Authors: Gabriele Weitz-Schmidt, Karl Welzenbach, Janet Dawson, Joerg Kallen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 45 Pg. 46764-71 (Nov 05 2004) ISSN: 0021-9258 [Print] United States
• PMID: 15304496 (Publication Type: Journal Article)

Chemical References

• Epitopes
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• LFA 878
• Lymphocyte Function-Associated Antigen-1
• Naphthalenes
• Oxazines
• Carrageenan
• Lovastatin

Topics

• Animals
• Binding Sites
• Blood (metabolism)
• Carrageenan (pharmacology)
• Cell Movement
• Dose-Response Relationship, Drug
• Edema
• Epitopes (chemistry)
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Inhibitory Concentration 50
• Jurkat Cells
• Leukocytes (cytology)
• Lovastatin (pharmacology)
• Lymphocyte Function-Associated Antigen-1 (chemistry, metabolism)
• Male
• Models, Chemical
• Models, Molecular
• Naphthalenes (chemistry, pharmacology)
• Oxazines (chemistry, pharmacology)
• Protein Binding
• Protein Conformation
• Protein Structure, Tertiary
• Rabbits
• Rats
• T-Lymphocytes (cytology)
• Time Factors
• X-Rays