Abstract
Though a variety of different non-canonical nucleic acids conformations have been recognized, G-quadruplex structures are probably the structural motifs most commonly found within known oligonucleotide-based aptamers. This could be ascribed to several factors, as their large conformational diversity, marked responsiveness of their folding/unfolding processes to external stimuli, high structural compactness and chemo-enzymatic and thermodynamic stability. A number of G-quadruplex-forming oligonucleotides having relevant in vitro anti-HIV activity have been discovered in the last two decades through either SELEX or rational design approaches. Improved aptamers have been obtained by chemical modifications of natural oligonucleotides, as terminal conjugations with large hydrophobic groups, replacement of phosphodiester linkages with phosphorothioate bonds or other surrogates, insertion of base-modified monomers, etc. In turn, detailed structural studies have elucidated the peculiar architectures adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. An overview of the state-of-the-art knowledge of the relevance of putative G-quadruplex forming sequences within the viral genome and of the most studied G-quadruplex-forming aptamers, selectively targeting HIV proteins, is here presented.
Highlights
Complete sequencing of the human genome revealed the presence of ~300,000 distinct sites that can potentially form G-quadruplex (G4) structures [1]
In this review, focused on Human ImmunodeficiencyVirus (HIV), a general overview of the potential role of the G4 structures in the viral life cycle is presented, followed by an extensive discussion on the strategies described in the literature to design and identify effective antiviral agents based on various types of G4-forming oligonucleotide (ON) aptamers
In HIV long terminal repeat (LTR) promoter (Figure 2) highly conserved G-rich DNA sequences corresponding to Sp1 and NF-κB binding sites were found to potentially fold into four mutually exclusive G-quadruplex topologies; notably, the equilibrium between these conformations plays a prominent role in regulating promoter activity [16,17]
Summary
Complete sequencing of the human genome revealed the presence of ~300,000 distinct sites that can potentially form G-quadruplex (G4) structures [1]. Other mammals, yeasts and prokaryotic cells exhibit putative G-quadruplex forming sequences which could act as regulatory elements in regions proximal to the transcription start sites of protein-coding genes. Even other organisms, such as viruses, have developed analogous potential regulatory mechanisms. In this review, focused on HIV, a general overview of the potential role of the G4 structures in the viral life cycle is presented, followed by an extensive discussion on the strategies described in the literature to design and identify effective antiviral agents based on various types of G4-forming oligonucleotide (ON) aptamers
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