Protein design of an HIV-1 entry inhibitor.
Human immunodeficiency virus type-1 (HIV-1) membrane fusion is promoted by the formation of a trimer-of-hairpins structure that brings the amino- and carboxyl-terminal regions of the gp41 envelope glycoprotein ectodomain into close proximity. Peptides derived from the carboxyl-terminal region (called C-peptides) potently inhibit HIV-1 entry by binding to the gp41 amino-terminal region. To test the converse of this inhibitory strategy, we designed a small protein, denoted 5-Helix, that binds the C-peptide region of gp41. The 5-Helix protein displays potent (nanomolar) inhibitory activity against diverse HIV-1 variants and may serve as the basis for a new class of antiviral agents. The inhibitory activity of 5-Helix also suggests a strategy for generating an HIV-1 neutralizing antibody response that targets the carboxyl-terminal region of the gp41 ectodomain.
Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. kimadmin@wi.mit.edu
M J
MJ
Root
M S
MS
Kay
P S
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Kim
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D015726:Giant Cells / Q000187:drug effects; D015483:HIV Antibodies / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects*; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D010455:Peptides; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
C420917:5-helix protein, synthetic; D019380:Anti-HIV Agents; D002352:Carrier Proteins; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins