Recognition of HIV TAR RNA by triazole linked neomycin dimers

A series of neomycin dimers have been synthesized using ‘click chemistry’ with varying linker functionality and length to target the TAR RNA region of HIV virus. TAR (trans activation response) RNA region, a 59 base pair stem loop structure located at 5′-end of all nascent HIV-1 transcripts interacts with a key regulatory protein, Tat, and necessitates the replication of HIV-1 virus. Neomycin, an aminosugar, has been shown to exhibit more than one binding site with HIV TAR RNA. Multiple TAR binding sites of neomycin prompted us to design and synthesize a small library of neomycin dimers using click chemistry. The binding between neomycin dimers and HIV TAR RNA was characterized using spectroscopic techniques including FID (Fluorescent Intercalator Displacement) titration and UV-thermal denaturation. UV thermal denaturation studies demonstrate that neomycin dimer binding increase the melting temperature (Tm) of the HIV TAR RNA up to 10 °C. Ethidium bromide displacement titrations revealed nanomolar IC50 between neomycin dimers and HIV TAR RNA, whereas with neomycin, a much higher IC50 in the micromolar range is observed.

Graphical abstractA series of neomycin dimers have been synthesized using ‘click chemistry’ to target the HIV virus TAR (trans activation response) RNA region. The neomycin dimers were synthesized in high yields and show a strong stabilizing effect on HIV TAR RNA, when compared to neomycin.Figure optionsDownload full-size imageDownload as PowerPoint slide