Structure-based design of peptides that recognize the CD4 binding domain of HIV-1 gp120.
METHODS
Envelope protein-specific antiviral peptides, called mucibodies, that can specifically recognize and bind to the surface unit protein gp120 of HIV-1 were designed. The initial mucibody binding target was the V3 loop of HIV-1 gp120. Here, the gp120-CD4 binding domain was chosen as the site of mucibody binding. The CD4 binding domain of gp120 is known to be a conformational epitope and is involved in the earliest events of viral entry into many cells.


METHODS
The design of the mucibody antivirals was based on previous observations that antibody complementarity determining regions (CDR) are generally similar to the repeating loops or knob structures found in the 20-residue tandem repeat domain of human mucin MUC1. The heavy chain CDR3 from the bacteriophage display antibody b12 was used to construct two mucibodies, b12-CDR1 and b12-26.


RESULTS
Peptides corresponding to three tandem repeats were shown to bind directly to the CD4 binding domain of HIV-1 gp120 in a solid-phase enzyme-linked immunosorbent assay. These mucibody peptides also disrupted the gp120-CD4 interaction in a solution-phase inhibition assay. Finally, mucibodies neutralized primary and laboratory macrophage-tropic isolates of HIV-1.


CONCLUSIONS
There is a potential for medical use of these peptides as topical vaginal microbicides in preventing HIV-1 transmission during sexual contact. These results also suggest that multivalent, non-immunogenic binding proteins of virtually any specificity could be constructed for use in therapeutic applications involving infectious diseases and immune system dysfunction.
Fontenot
J D
JD
Population Council, Center for Biomedical Research, New York, New York 10021, USA.
Tan
X
X
Phillips
D M
DM
D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000737:chemistry*; D015488:HIV Antigens / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1; D006801:Humans; D009077:Mucins / Q000737:chemistry; D009500:Neutralization Tests; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D020080:Tandem Repeat Sequences
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D009077:Mucins; D010455:Peptides