The first stage of the HIV infection requires the entry of HIV virus into host cells. This stage involves the sequential interaction of the viral envelope glycoprotein gp120 with the CD4 glycoprotein and chemokine receptors on the host cell surface. The third hyper variable region of gp120 (V3 loop) has been identified as the pivotal component of the co-receptor binding site. The V3 loop typically consists of a 35 aminoacids loop closed by two cysteines forming a disulphide bridge. As emerged from the crystal structure of gp120 complexed with the CD4 receptor and a neutralizing antibody, the V3 loop protrudes from the protein core and is involved in the binding with the co-receptor. Given the important role played by the V3 loop for HIV-1 infection and pathogenesis many efforts are being devoted to the development of drugs targeted against it. Among the most promising alternatives is the use of aptamer technology. The first anti-HIV aptamers targeted against the V3 loop appeared in the literature in 1994 when H. Hotoda (SA-1042) and J.R. Wyatt (ISIS 5320) independently showed the ability of nucleases-resistant quadruplex-forming DNA aptamers to bind the V3 loop of gp120 thus protecting CD4+ cells from HIV infection. In 2010, considering that all the gp120-binding aptamers present in the literature needed chemical modifications to improve their resistance against nucleases and to improve the kinetics of quadruplex formation, we began a study aimed at the synthesis of a series of new monomolecular analogues of SA-1042 by exploiting the Tetra-End-Linker (TEL) strategy proposed by us in 2004 [3]. In the last four years several TEL-aptamers differing for the TEL size, the polarity of the ODN strands and lipophilic ending groups or for the ODN sequence and length have been synthesized in our laboratories. The main results obtained by chemical, biophysical, biological and SAR investigation are reported in this communication. The EC50 of new TEL-aptamers is as low as 0.039 ??M.

Anti HIV activity of monomolecular tetra-end-linked analogues of the SA-1042 aptamer targeted against the viral envelope glycoprotein gp120

BORBONE, NICOLA;OLIVIERO, GIORGIA;D'ATRI, VALENTINA;NICI, FABRIZIA;D'ERRICO, STEFANO;MAYOL, LUCIANO;PICCIALLI, VINCENZO;PICCIALLI, GENNARO
2014

Abstract

The first stage of the HIV infection requires the entry of HIV virus into host cells. This stage involves the sequential interaction of the viral envelope glycoprotein gp120 with the CD4 glycoprotein and chemokine receptors on the host cell surface. The third hyper variable region of gp120 (V3 loop) has been identified as the pivotal component of the co-receptor binding site. The V3 loop typically consists of a 35 aminoacids loop closed by two cysteines forming a disulphide bridge. As emerged from the crystal structure of gp120 complexed with the CD4 receptor and a neutralizing antibody, the V3 loop protrudes from the protein core and is involved in the binding with the co-receptor. Given the important role played by the V3 loop for HIV-1 infection and pathogenesis many efforts are being devoted to the development of drugs targeted against it. Among the most promising alternatives is the use of aptamer technology. The first anti-HIV aptamers targeted against the V3 loop appeared in the literature in 1994 when H. Hotoda (SA-1042) and J.R. Wyatt (ISIS 5320) independently showed the ability of nucleases-resistant quadruplex-forming DNA aptamers to bind the V3 loop of gp120 thus protecting CD4+ cells from HIV infection. In 2010, considering that all the gp120-binding aptamers present in the literature needed chemical modifications to improve their resistance against nucleases and to improve the kinetics of quadruplex formation, we began a study aimed at the synthesis of a series of new monomolecular analogues of SA-1042 by exploiting the Tetra-End-Linker (TEL) strategy proposed by us in 2004 [3]. In the last four years several TEL-aptamers differing for the TEL size, the polarity of the ODN strands and lipophilic ending groups or for the ODN sequence and length have been synthesized in our laboratories. The main results obtained by chemical, biophysical, biological and SAR investigation are reported in this communication. The EC50 of new TEL-aptamers is as low as 0.039 ??M.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/597185
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