Peptides Corresponding to a Predictive α-Helical Domain of Human Immunodeficiency Virus Type 1 gp41 are Potent Inhibitors of Virus Infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 21; pp. 9770 - 9774
• Main Authors: Wild, Carl T., Shugars, Diane C., Greenwell, Teresa K., McDanal, Charlene B., Matthews, Thomas J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 11.10.1994; National Acad Sciences
• Subjects: AIDS/HIV; Amino Acid Sequence; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antivirals; Cell fusion; Cell Line; Cell lines; Giant cells; Giant Cells - drug effects; HIV 1; HIV 2; HIV Envelope Protein gp41 - chemistry; HIV-1 - drug effects; HIV-1 - isolation & purification; HIV-1 - physiology; HIV-2 - physiology; human immunodeficiency virus 1; Humans; Infections; Molecular Sequence Data; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Polymerase Chain Reaction; Protein Structure, Secondary; Proteins; Proviruses - drug effects; Proviruses - physiology; Sequence Homology, Amino Acid; Virus Replication - drug effects; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.21.9770

To define the role of the human immunodeficiency virus type 1 (HIV-1) envelope proteins in virus infection, a series of peptides were synthesized based on various regions of the HIV-1 transmembrane protein gp41. One of these peptides, DP-178, corresponding to a region predictive of α-helical secondary structure (residues 643-678 of the HIV-1LAIisolate), has been identified as a potent antiviral agent. This peptide consistently blocked 100% of virus-mediated cell-cell fusion at <5 ng/ml (IC90≈ 1.5 ng/ml) and gave an ≈ 10 times reduction in infectious titer of cell-free virus at ≈ 80 ng/ml. The inhibitory activity was observed at peptide concentrations ≈104to 105times lower than those at which cytotoxicity and cytostasis were detected. Peptide-mediated inhibition is HIV-1 specific in that ≈102to 103times more peptide was required for inhibition of a human immunodeficiency virus type 2 isolate. Further experiments showed that DP-178 exhibited antiviral activity against both prototypic and primary HIV-1 isolates. As shown by PCR analysis of newly synthesized proviral DNA, DP-178 blocks an early step in the virus life cycle prior to reverse transcription. Finally, we discuss possible mechanisms by which DP-178 may exert its inhibitory activity.