title: Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide.
abstract: 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.
authors: Institute of Virology, University of Ulm, 89081 Ulm, Germany.
authors: Jan
authors: J
authors: Münch
authors: Ludger
authors: L
authors: Ständker
authors: Knut
authors: K
authors: Adermann
authors: Axel
authors: A
authors: Schulz
authors: Michael
authors: M
authors: Schindler
authors: Raghavan
authors: R
authors: Chinnadurai
authors: Stefan
authors: S
authors: Pöhlmann
authors: Chawaree
authors: C
authors: Chaipan
authors: Thorsten
authors: T
authors: Biet
authors: Thomas
authors: T
authors: Peters
authors: Bernd
authors: B
authors: Meyer
authors: Dennis
authors: D
authors: Wilhelm
authors: Hong
authors: H
authors: Lu
authors: Weiguo
authors: W
authors: Jing
authors: Shibo
authors: S
authors: Jiang
authors: Wolf-Georg
authors: WG
authors: Forssmann
authors: Frank
authors: F
authors: Kirchhoff
mesh_terms: 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*
chemical_list: D001798:Blood Proteins; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C519920:VIRIP peptide, human; D000515:alpha 1-Antitrypsin