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Insight into the mechanisms of aminoglycoside derivatives interaction with HIV‐1 entry steps and viral gene transcription
Author(s) -
Lapidot Aviva,
Berchanski Alexander,
Borkow Gadi
Publication year - 2008
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2008.06657.x
Subject(s) - transcription (linguistics) , aminoglycoside , human immunodeficiency virus (hiv) , gene , virology , chemistry , biology , computational biology , microbiology and biotechnology , genetics , antibiotics , philosophy , linguistics
In recent years, based on peptide models of HIV‐1 RNA binding, NMR structures of Tat‐responsive element–ligand complexes and aminoglycoside–RNA interactions, and HIV‐1 Tat structure, we have designed and synthesized aminoglycoside–arginine conjugates (AACs) and aminoglycoside poly‐arginine conjugates (APACs), to serve as Tat mimetics. These novel molecules inhibit HIV‐1 infectivity with 50% effective concentration values in the low micromolar range, the most potent compounds being the hexa‐arginine–neomycin B and nona‐ d ‐arginine–neomycin conjugates. Importantly, these compounds, in addition to acting as Tat antagonists, inhibit HIV‐1 infectivity by blocking several steps in HIV‐1 cell entry. The AACs and APACs inhibit HIV‐1 cell entry by interacting with gp120 at the CD4‐binding site, by interacting with CXCR4 at the binding site of the CXCR4 mAb 12G5, and apparently by interacting with transient structures of the ectodomain of gp41. In the current review, we discuss the mechanisms of anti‐HIV‐1 activities of these AACs, APACs and other aminoglycoside derivatives in detail. Targeting several key processes in the viral life cycle by the same compound not only may increase its antiviral efficacy, but more importantly, may reduce the capacity of the virus to develop resistance to the compound. AACs and APACs may thus serve as leading compounds for the development of multitargeting novel HIV‐1 inhibitors.