Selective alpha4beta7 integrin antagonists and their potential as antiinflammatory agents.
The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin alpha4beta7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of alpha4beta7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that alpha4beta7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective alpha4beta7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded alpha4beta7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for alpha4beta7 by more than 500-fold to afford a potent and selective alpha4beta1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for alpha4beta7 compared to other integrins.
Department of Bioorganic Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Nathan J P
NJ
Dubree
Dean R
DR
Artis
Georgette
G
Castanedo
James
J
Marsters
Daniel
D
Sutherlin
Lisa
L
Caris
Kevin
K
Clark
Susan M
SM
Keating
Maureen H
MH
Beresini
Henry
H
Chiu
Sherman
S
Fong
Henry B
HB
Lowman
Nicholas J
NJ
Skelton
David Y
DY
Jackson
D000409:Alanine / Q000737:chemistry; D019943:Amino Acid Substitution; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015815:Cell Adhesion Molecules; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003092:Colitis / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D007136:Immunoglobulins / Q000737:chemistry; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007422:Intestines / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018716:Molecular Mimicry; D009088:Mucoproteins / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry*; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016201:Receptors, Lymphocyte Homing / Q000737:chemistry; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; D010456:Peptides, Cyclic; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7; D000409:Alanine