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.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

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.

J Biol Chem. 1999 Feb 5;274(6):3789-96. Unique Identifier : AIDSLINE GENBANK/AJ005355
Monnet C; Laune D; Laroche-Traineau J; Biard-Piechaczyk M; Briant L; Bes C; Pugniere M; Mani JC; Pau B; Cerutti M; Devauchelle G; Devaux C; Granier C; Chardes T; Faculte de Pharmacie, 15 Avenue Charles Flahault, 34060; Montpellier, France.

Abstract: 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 beta-galactosidase gene expression in the HeLa P4 HIV-1 long terminal repeat beta-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.

Keywords: JOURNAL ARTICLE Amino Acid Sequence Antibodies, Monoclonal/*CHEMISTRY Antigens, CD4/*IMMUNOLOGY Base Sequence DNA Primers Gene Expression Regulation, Viral/*IMMUNOLOGY Hela Cells Human HIV-1/*GENETICS Immunoglobulin Variable Region/IMMUNOLOGY Molecular Sequence Data Peptide Fragments/*IMMUNOLOGY *Promoter Regions (Genetics) Support, Non-U.S. Gov't
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A9950853

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