期刊
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
卷 47, 期 4, 页码 311-316出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijantimicag.2016.01.016
关键词
HIV; Aptamer; Antiretroviral drug; Attachment
资金
- Bill and Melinda Gates Foundation [GCE] [OPP1035881, OPP1097238]
- European Research Council [ERC Consolidator grant] [615879]
- Italian Ministry of University and Research [RBID082ATK_001]
- KU Leuven Geconcerteerde Onderzoeksactie [GOA] [15-019-TBA]
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. (C) 2016 The Authors. Published by Elsevier B.V.
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