Inhibition of HIV-1 by a peptide ligand of the genomic RNA packaging signal Psi.
The interaction of the nucleocapsid NCp7 of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein with the RNA packaging signal Psi ensures specific encapsidation of the dimeric full length viral genome into nascent virus particles. Being an essential step in the HIV-1 replication cycle, specific genome encapsidation represents a promising target for therapeutic intervention. We previously selected peptides binding to HIV-1 Psi-RNA or stem loops (SL) thereof by phage display. Herein, we describe synthesis of peptide variants of the consensus HWWPWW motif on membrane supports to optimize Psi-RNA binding. The optimized peptide, psi-pepB, was characterized in detail with respect to its conformation and binding properties for the SL3 of the Psi packaging signal by NMR and tryptophan fluorescence quenching. Functional analysis revealed that psi-pepB caused a strong reduction of virus release by infected cells as monitored by reduced transduction efficiencies, capsid p24 antigen levels, and electron microscopy. Thus, this peptide shows antiviral activity and could serve as a lead compound to develop new drugs targeting HIV-1.
Dietz
Julia
J
Georg-Speyer-Haus, Institute for Biomedical Research, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany.
Koch
Joachim
J
Kaur
Ajit
A
Raja
Chinnappan
C
Stein
Stefan
S
Grez
Manuel
M
Pustowka
Anette
A
Mensch
Sarah
S
Ferner
Jan
J
Möller
Lars
L
Bannert
Norbert
N
Tampé
Robert
R
Divita
Gilles
G
Mély
Yves
Y
Schwalbe
Harald
H
Dietrich
Ursula
U
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D015683:Gene Products, gag / Q000737:chemistry*; D016679:Genome, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D012367:RNA, Viral / Q000737:chemistry*; D019065:Virus Assembly
D019380:Anti-HIV Agents; D015683:Gene Products, gag; D010455:Peptides; D012367:RNA, Viral