Structural Studies and Biological Evaluation of T30695 Variants Modified with Single Chiral Glycerol-T Reveal the Importance of LEDGF/p75 for the Aptamer Anti-HIV-Integrase Activities

Publication date: Available online 7 November 2018Source: Biochimica et Biophysica Acta (BBA) - General SubjectsAuthor(s): Elisa Rivieccio, Luciana Tartaglione, Veronica Esposito, Carmela Dell'Aversano, P.C. Koneru, Maria Scuotto, Antonella Virgilio, Luciano Mayol, Mamuka Kvaratskhelia, Michela VarraAbstractSome G-quadruplex (GQ) forming aptamers, such as T30695, exhibit particularly promising properties among the potential anti-HIV drugs. T30695 G-quadruplex binds to HIV-1 integrase (IN) and inhibits its activity during 3′-end processing at nanomolar concentrations. Herein we report a study concerning six T30695-GQ variants, in which the R or S chiral glycerol T, singly replaced the thymine residues at the T30695 G-quadruplex loops. CD melting, EMSA and HMRS experiments provided information about the thermal stability and the stoichiometry of T30695-GQ variants, whereas CD and 1H NMR studies were performed to evaluate the effects of the modifications on T30695-GQ topology. Furthermore, LEDGF/p75 dependent and independent integration assays were carried out to evaluate how T loop modifications impact T30695-GQ biological activities. The obtained results showed that LEDGF/p75 adversely affects the potencies of T30695 and its variants. The IN inhibitory activities of the modified aptamers also depended on the position and on the chirality (R or S) of glycerol T loop in the GQ, mostly regardless of the G-quadruplex stabilities. In view of our and literature data, we sugges...
Source: Biochimica et Biophysica Acta (BBA) General Subjects - Category: Biochemistry Source Type: research