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J Biol Chem, Vol. 274, Issue 6, 3789-3796, February 5, 1999

Synthetic Peptides Derived from the Variable Regions of an Anti-CD4 Monoclonal Antibody Bind to CD4 and Inhibit HIV-1 Promoter Activation in Virus-infected Cells

Céline Monnet, Daniel Laune, Jeanny Laroche-Traineau, Martine Biard-Piechaczyk^§, Laurence Briant^§, Cédric Bès, Martine Pugnière, Jean-Claude Mani, Bernard Pau, Martine Cerutti^¶, Gérard Devauchelle^¶, Christian Devaux^§, Claude Granier, and Thierry Chardès^¶

From  CNRS UMR 9921, Faculté de Pharmacie, 15 Avenue Charles Flahault and ^§ CNRS UPR 1086, CRBM-Laboratoire Infections Rétrovirales et Signalisation Cellulaire, 34060 Montpellier, France and ^¶ INRA-CNRS URA 2209, Laboratoire de Pathologie Comparée, 30380 Saint-Christol-Lez-Alès, France

The monoclonal antibody (mAb) ST40, specific for the immunoglobulin complementarity-determining region (CDR) 3-like loop in domain 1 of the CD4 molecule, inhibits human immunodeficiency virus type 1 (HIV-1) promoter activity and viral transcription in HIV-infected cells. To design synthetic peptides from the ST40 paratope that could mimic these biological properties, a set of 220 overlapping 12-mer peptides frameshifted by one residue, corresponding to the deduced ST40 amino acid sequence, was synthesized by the Spot method and tested for binding to recombinant soluble CD4 antigen. Several peptides that included in their sequences amino acids from the CDRs of the antibody and framework residues flanking the CDRs were found to bind soluble CD4. Eleven paratope-derived peptides (termed CM1-CM11) were synthesized in a cyclic and soluble form. All the synthetic peptides showed CD4 binding capacity with affinities ranging from 1.6 to 86.4 nM. Moreover, peptides CM2, CM6, CM7, CM9, and CM11 were able to bind a cyclic peptide corresponding to the CDR3-like loop in domain 1 of CD4 (amino acids 81-92 of CD4). Peptide CM9 from the light chain variable region of mAb ST40 and, to a lesser extent, peptides CM2 and CM11 were able to inhibit HIV-1 promoter long terminal repeat-driven -galactosidase gene expression in the HeLa P4 HIV-1 long terminal repeat -galactosidase indicator cell line infected with HIV-1. The binding of mAb ST40 to CD4 was also efficiently displaced by peptides CM2, CM9, and CM11. Our results indicate that the information gained from a systematic exploration of the antigen binding capacity of synthetic peptides from immunoglobulin variable sequences can lead to the identification of bioactive paratope-derived peptides of potential pharmacological interest.

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