Improvement of the activity of the anti-HIV-1 integrase aptamer T30175 by introducing a modified thymidine into the loops

Scientific Reports
Antonella VirgilioAldo Galeone

Abstract

In this paper, we report our investigations on analogues of the anti-human immunodeficiency virus type 1 (HIV-1) integrase (IN) aptamer T30175 in which the individual thymidines forming the loops were replaced by 5-hydroxymethyl-2'-deoxyuridine residues (H). Circular dichroism, nuclear magnetic resonance and gel electrophoresis investigations clearly indicated that all the modified aptamers preserve the ability to form the original 5'-5' end-stacked head-to-head dimeric G-quadruplex structure, in which each G-quadruplex adopts a parallel arrangement and is characterized by three G-tetrads, three propeller loops and one bulge-loop. All the modified aptamers were tested in an IN inhibition LEDGF-independent assay. While the modified aptamers INTB-H13 and INTB-H17 showed IC50 values comparable with that of the parent aptamer (INTB-nat), analogues INTB-H2, INTB-H5 and, to a lesser extent, INTB-H9 showed a higher ability to inhibit the HIV IN than the unmodified aptamer. Molecular modelling studies evaluating the aptamer/HIV IN interaction highlighted the ability of the modified thymidines to establish several contacts with the target protein. All the data point to the importance of loops in the aptamer/target interaction and sugges...Continue Reading

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Citations

Oct 3, 2018·Pharmaceuticals·Philisiwe Fortunate MolefeAbidemi Paul Kappo
Aug 13, 2020·International Journal of Molecular Sciences·Veronica EspositoAldo Galeone
Oct 11, 2020·International Journal of Molecular Sciences·Chioma Izzi-EngbeayaWaljit S Dhillo
May 1, 2021·International Journal of Molecular Sciences·Tae-Hyeong Kim, Seong-Wook Lee

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Methods Mentioned

BETA
electrophoresis
NMR
Fluorescence
X-ray

Software Mentioned

FF14SB
AMBER
HEX

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