New anti-HIV aptamers with enhanced activity based on tetra-end-linked G-quadruplex-forming oligonucleotides

The first stage of the HIV infection requires the entry of human immunodeficiency virus (HIV) into host cells. This stage involves the sequential interaction of the virion surface glycoprotein gp120 with the CD4 glycoprotein and a chemokine receptor on the host cell surface.1 The CD4 glycoprotein is expressed on the surface of T-lymphocytes, monocytes, dendritic cells and brain microglia, and its expression makes these cells a target for HIV in vivo. The third variable region of gp120 – known as V3-loop – is a pivotal component of the co-receptor binding site, thus making it a target for pharmaceutical intervention. The first anti-HIV aptamers targeted against the V3 loop appeared in the literature in 2004, when H. Hotoda (SA-1042)2 and J. R. Wyatt (ISIS 5320)3 indipendently showed that chemically-modified selected G-quadruplex-forming ODN aptamers are capable to bind the V3 loop of gp120, thus protecting host cells from HIV infection. In the following years several analogs of SA-1042 have been proposed with the aim to improve both the anti-HIV activity and resistance to nucleases. This communication reports on the synthesis and biophysical, biological and SAR studies of a small library of new analogs of SA-1042 based on G-quadruplex-forming Tetra-End-Linked (TEL) oligonucleotides.4 The new aptamers showed EC50 values against HIV-1 in the range of 0.04-0.15 µM, as well as affinities for the HIV-1 gp120 envelope at the same order of magnitude.