Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures.
Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.
Bolin
D R
DR
Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
Swain
A L
AL
Sarabu
R
R
Berthel
S J
SJ
Gillespie
P
P
Huby
N J
NJ
Makofske
R
R
Orzechowski
L
L
Perrotta
A
A
Toth
K
K
Cooper
J P
JP
Jiang
N
N
Falcioni
F
F
Campbell
R
R
Cox
D
D
Gaizband
D
D
Belunis
C J
CJ
Vidovic
D
D
Ito
K
K
Crowther
R
R
Kammlott
U
U
Zhang
X
X
Palermo
R
R
Weber
D
D
Guenot
J
J
Nagy
Z
Z
Olson
G L
GL
D017951:Antigen Presentation; D001667:Binding, Competitive; D002241:Carbohydrates / Q000737:chemistry; D002401:Cathepsin B / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006684:HLA-DR Antigens / Q000737:chemistry*; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D018716:Molecular Mimicry; D010452:Peptide Biosynthesis; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D002241:Carbohydrates; D004151:Dipeptides; D006684:HLA-DR Antigens; D002401:Cathepsin B