Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection.
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 alpha-helical secondary structure (residues 643-678 of the HIV-1LAI isolate), has been identified as a potent antiviral agent. This peptide consistently blocked 100% of virus-mediated cell-cell fusion at < 5 ng/ml (IC90 approximately 1.5 ng/ml) and gave an approximately 10 times reduction in infectious titer of cell-free virus at approximately 80 ng/ml. The inhibitory activity was observed at peptide concentrations approximately 10(4) to 10(5) times lower than those at which cytotoxicity and cytostasis were detected. Peptide-mediated inhibition is HIV-1 specific in that approximately 10(2) to 10(3) times 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.
Wild
C T
CT
Department of Surgery, Duke University Medical Center, Durham, NC 27710.
Shugars
D C
DC
Greenwell
T K
TK
McDanal
C B
CB
Matthews
T J
TJ
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015726:Giant Cells / Q000187:drug effects; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D015498:HIV-2 / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D017433:Protein Structure, Secondary; D011533:Proviruses / Q000187:drug effects / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D010455:Peptides