Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide.
A variety of molecules in human blood have been implicated in the inhibition of HIV-1. However, it remained elusive which circulating natural compounds are most effective in controlling viral replication in vivo. To identify natural HIV-1 inhibitors we screened a comprehensive peptide library generated from human hemofiltrate. The most potent fraction contained a 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of alpha1-antitrypsin, the most abundant circulating serine protease inhibitor. We found that VIRIP inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. Further analysis demonstrated that VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and showed that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Thus, as a highly specific natural inhibitor of the HIV-1 gp41 fusion peptide, VIRIP may lead to the development of another class of antiretroviral drugs.
Münch
Jan
J
Institute of Virology, University of Ulm, 89081 Ulm, Germany.
Ständker
Ludger
L
Adermann
Knut
K
Schulz
Axel
A
Schindler
Michael
M
Chinnadurai
Raghavan
R
Pöhlmann
Stefan
S
Chaipan
Chawaree
C
Biet
Thorsten
T
Peters
Thomas
T
Meyer
Bernd
B
Wilhelm
Dennis
D
Lu
Hong
H
Jing
Weiguo
W
Jiang
Shibo
S
Forssmann
Wolf-Georg
WG
Kirchhoff
Frank
F
D000595:Amino Acid Sequence; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D001798:Blood Proteins; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C519920:VIRIP peptide, human; D000515:alpha 1-Antitrypsin