Publication Date:
2002-02-09
Description:
The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gadek, T R -- Burdick, D J -- McDowell, R S -- Stanley, M S -- Marsters, J C Jr -- Paris, K J -- Oare, D A -- Reynolds, M E -- Ladner, C -- Zioncheck, K A -- Lee, W P -- Gribling, P -- Dennis, M S -- Skelton, N J -- Tumas, D B -- Clark, K R -- Keating, S M -- Beresini, M H -- Tilley, J W -- Presta, L G -- Bodary, S C -- New York, N.Y. -- Science. 2002 Feb 8;295(5557):1086-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioorganic Chemistry, Genentech, One DNA Way, South San Francisco, CA 94080, USA. trg@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11834839" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Anti-Inflammatory Agents, Non-Steroidal/chemical
;
synthesis/chemistry/metabolism/pharmacology
;
Cyclosporine/pharmacology
;
Dermatitis, Irritant/drug therapy
;
Dinitrofluorobenzene
;
Drug Design
;
Enzyme-Linked Immunosorbent Assay
;
Epitopes
;
Female
;
Humans
;
Immunoglobulin Fab Fragments/immunology/pharmacology
;
Immunosuppressive Agents/chemical synthesis/chemistry/metabolism/*pharmacology
;
Intercellular Adhesion Molecule-1/chemistry/*immunology/*metabolism
;
Lymphocyte Culture Test, Mixed
;
Lymphocyte Function-Associated Antigen-1/immunology/*metabolism
;
Mice
;
Mice, Inbred BALB C
;
Molecular Mimicry
;
Mutagenesis
;
Protein Structure, Secondary
;
Structure-Activity Relationship
;
Thiophenes/*chemical synthesis/chemistry/metabolism/*pharmacology
;
beta-Alanine/analogs & derivatives/*chemical
;
synthesis/chemistry/metabolism/*pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
