A peptide mimetic of an anti-CD4 monoclonal antibody by rational design.
The development of rational methods to design 'continuous' sequence mimetics of discontinuous regions of protein sequence has, to now, been only marginally successful. This has been largely due to the difficulty of constraining the recognition elements of a mimetic structure to the relative conformational and spatial orientations present in the parent molecule. Using peptide mapping to determine 'active' antigen recognition residues, molecular modeling, and a molecular dynamics trajectory analysis, we have developed a peptide mimic of an anti-CD4 antibody, containing antigen contact residues from multiple CDRs. The design described is a 27-residue peptide formed by juxtaposition of residues from 5 CDR regions. It displays an affinity for the antigen (CD4) of 0.9nM, compared to 2nM for the parent antibody ST40. Nevertheless, the mimetic shows low biological activity in an anti-retroviral assay.
Casset
Florence
F
Synt:em, Parc Scientifique Georges Besse, FR-30035 1, Ni;mes Cédex, France.
Roux
Florence
F
Mouchet
Patrick
P
Bes
Cedric
C
Chardes
Thierry
T
Granier
Claude
C
Mani
Jean-Claude
JC
Pugnière
Martine
M
Laune
Daniel
D
Pau
Bernard
B
Kaczorek
Michel
M
Lahana
Roger
R
Rees
Anthony
A
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D010455:Peptides