Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule.
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.
Gadek
T R
TR
Department of Bioorganic Chemistry, Genentech, One DNA Way, South San Francisco, CA 94080, USA. trg@gene.com
Burdick
D J
DJ
McDowell
R S
RS
Stanley
M S
MS
Marsters
J C
JC
Paris
K J
KJ
Oare
D A
DA
Reynolds
M E
ME
Ladner
C
C
Zioncheck
K A
KA
Lee
W P
WP
Gribling
P
P
Dennis
M S
MS
Skelton
N J
NJ
Tumas
D B
DB
Clark
K R
KR
Keating
S M
SM
Beresini
M H
MH
Tilley
J W
JW
Presta
L G
LG
Bodary
S C
SC
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D017453:Dermatitis, Irritant / Q000188:drug therapy; D004139:Dinitrofluorobenzene; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D016296:Mutagenesis; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
C448301:2-(4-(3-hydroxy-3-(hydroxyphenyl)propyl)-2,6-dichlorophenyl)carbomylamino-3-((thiophen-2-yl)carbonylamino)propanoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D013876:Thiophenes; D015091:beta-Alanine; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine; D004139:Dinitrofluorobenzene