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Int J Antimicrob Agents. 2016 Apr;47(4):311-6. doi: 10.1016/j.ijantimicag.2016.01.016. Epub 2016 Mar 11.

The G-quadruplex-forming aptamer AS1411 potently inhibits HIV-1 attachment to the host cell.

Author information

1
Department of Molecular Medicine, University of Padua, Padua, Italy.
2
Department of Molecular Medicine, University of Padua, Padua, Italy; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
3
KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.
4
Department of Molecular Medicine, University of Padua, Padua, Italy. Electronic address: sara.richter@unipd.it.

Abstract

AS1411 is a G-rich aptamer that forms a stable G-quadruplex structure and displays antineoplastic properties both in vitro and in vivo. This oligonucleotide has undergone phase 2 clinical trials. The major molecular target of AS1411 is nucleolin (NCL), a multifunctional nucleolar protein also present in the cell membrane where it selectively mediates the binding and uptake of AS1411. Cell-surface NCL has been recognised as a low-affinity co-receptor for human immunodeficiency virus type 1 (HIV-1) anchorage on target cells. Here we assessed the anti-HIV-1 properties and underlying mechanism of action of AS1411. The antiviral activity of AS1411 was determined towards different HIV-1 strains, host cells and at various times post-infection. Acutely, persistently and latently infected cells were tested, including HIV-1-infected peripheral blood mononuclear cells from a healthy donor. Mechanistic studies to exclude modes of action other than virus binding via NCL were performed. AS1411 efficiently inhibited HIV-1 attachment/entry into the host cell. The aptamer displayed antiviral activity in the absence of cytotoxicity at the tested doses, therefore displaying a wide therapeutic window and favourable selectivity indexes. These findings, besides validating cell-surface-expressed NCL as an antiviral target, open the way for the possible use of AS1411 as a new potent and promisingly safe anti-HIV-1 agent.

KEYWORDS:

Antiretroviral drug; Aptamer; Attachment; HIV

PMID:
27032748
PMCID:
PMC4840014
DOI:
10.1016/j.ijantimicag.2016.01.016
[Indexed for MEDLINE]
Free PMC Article

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