A small molecule agonist of an integrin, alphaLbeta2.
The binding of integrin alpha(L)beta(2) to its ligand intercellular adhesion molecule-1 is required for immune responses and leukocyte trafficking. Small molecule antagonists of alpha(L)beta(2) are under intense investigation as potential anti-inflammatory drugs. We describe for the first time a small molecule integrin agonist. A previously described alpha/beta I allosteric inhibitor, compound 4, functions as an agonist of alpha(L)beta(2) in Ca(2+) and Mg(2+)and as an antagonist in Mn(2+). We have characterized the mechanism of activation and its competitive and noncompetitive inhibition by different compounds. Although it stimulates ligand binding, compound 4 nonetheless inhibits lymphocyte transendothelial migration. Agonism by compound 4 results in accumulation of alpha(L)beta(2) in the uropod, extreme uropod elongation, and defective de-adhesion. Small molecule integrin agonists open up novel therapeutic possibilities.
Yang
Wei
W
CBR Institute for Biomedical Research, Departments of Pathology and Anesthesia, Harvard Medical School, Boston, Massachusetts 02115, USA.
Carman
Christopher V
CV
Kim
Minsoo
M
Salas
Azucena
A
Shimaoka
Motomu
M
Springer
Timothy A
TA
D000494:Allosteric Regulation; D000911:Antibodies, Monoclonal; D002413:Cations, Divalent / Q000378:metabolism / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020014:K562 Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000911:Antibodies, Monoclonal; D002413:Cations, Divalent; D016169:Lymphocyte Function-Associated Antigen-1; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1