Proline-rich tandem repeats of antibody complementarity-determining regions bind and neutralize human immunodeficiency virus type 1 particles.
The proline-rich tandem repeat domain of human mucin MUC1 forms an extended structure containing large repeating loops that are crested by a turn. We show that the repeating-loop structure of MUC1 can be replaced by an antibody complementarity-determining region loop of a human immunodeficiency virus type 1 (HIV-1)-specific neutralizing antibody to create a chimeric, multivalent, mucin-like, anti-HIV-1 compound. We used 8 residues of an antibody molecule to replace 8 of 20 residues of the MUC1 tandem-repeat sequence. The antiviral peptide discussed here contains three copies of a 20-residue tandem repeat, (IYYDYEEDPAPGSTAPPAHG)3, for a total of 60 residues. We demonstrate that the mucin-antibody chimera retains the binding specificity of the parent antibody (monoclonal antibody F58), GPGR of the HIV-1 gp120 V3 neutralizing epitope, and the ability to neutralize virus particles. In inhibition enzyme-linked immunosorbent assay, the mucin-antibody chimeric peptide could inhibit 71 to 84% of binding to a V3 loop peptide by monoclonal antibodies known to be specific for GPGR in the V3 loop. The mucin-antibody chimeric peptide could also inhibit monoclonal antibody binding to native gp120 captured from virus particles. In addition, the chimeric peptide neutralized the homologous HIV-IIIB virus in a standard neutralization assay. The methods of antiviral peptide design and construction presented here are general and theoretically limited only by the size of the antibody repertoire. This approach could be used to synthesize peptides for a variety of therapeutic applications.
Fontenot
J D
JD
The Population Council, New York, New York 10021, USA.
Zacharopoulos
V R
VR
Phillips
D M
DM
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology; D015483:HIV Antibodies / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000235:genetics*; D011392:Proline; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D012091:Repetitive Sequences, Nucleic Acid
D000998:Antiviral Agents; D015483:HIV Antibodies; D018396:Mucin-1; D011993:Recombinant Fusion Proteins; D011392:Proline