Inhibitory effects of archetypical nucleic acid ligands on the interactions of HIV-1 nucleocapsid protein with elements of Psi-RNA.
Disrupting the interactions between human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein and structural elements of the packaging signal (Psi-RNA) could constitute an ideal strategy to inhibit the functions of this region of the genome leader in the virus life cycle. We have employed electrospray ionization (ESI) Fourier transform mass spectrometry (FTMS) to assess the ability of a series of nucleic acid ligands to bind selected structures of Psi-RNA and inhibit their specific interactions with NC in vitro. We found that the majority of the ligands included in the study were able to form stable non-covalent complexes with stem-loop 2, 3 and 4 (SL2-4), consistent with their characteristic nucleic acid binding modes. However, only aminoglycosidic antibiotics were capable of dissociating preformed NC*SL3 and NC*SL4 complexes, but not NC*SL2. The apparent specificity of these inhibitory effects is closely dependent on distinctive structural features of the different NC*RNA complexes. The trends observed for the IC50 values correlate very well with those provided by the ligand binding affinities and the dissociation constants of target NC*RNA complexes. This systematic investigation of archetypical nucleic acid ligands provides a valid framework to support the design of novel ligand inhibitors for HIV-1 treatment.
Turner
Kevin B
KB
Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21228, USA.
Hagan
Nathan A
NA
Fabris
Daniele
D
D000595:Amino Acid Sequence; D000617:Aminoglycosides / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D036022:Capsid Proteins / Q000737:chemistry* / Q000378:metabolism; D015683:Gene Products, gag / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D055672:Static Electricity; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus
D000617:Aminoglycosides; D019380:Anti-HIV Agents; D036022:Capsid Proteins; D015683:Gene Products, gag; D008024:Ligands; C071884:NCP7 protein, Human immunodeficiency virus 1; D012367:RNA, Viral; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus