DNA Quadruplex-Based Inhibitor With Flexible Fragments at the 3' Terminal Shows Enhanced Anti-HIV-1 Fusion Activity.

Chemically optimizing the molecular structure of aptamers may enhance properties such as biological activity or metabolic stability. DNA quadruplex-based HIV-1 fusion inhibitors were found to interact with HIV-1 surface glycoprotein in aptamer mode. In this work, a series of quadruplex-based HIV-1 fusion inhibitors with flexible oligodeoxynucleotide fragments at the 3' terminal was discovered. The flexible extension did not greatly influence quadruplex formation at the 5'-end. Increasing the length of the flexible fragment may increase antifusion activity. Compared with a traditional inhibitor, d(TGGGAG), these novel inhibitors showed enhanced interaction with HIV-1 glycoproteins gp120 and gp41, which increased inhibition of 6-helical bundle formation during the course of virus fusion. These inhibitors also showed improved stability, compared with natural oligodeoxynucleotide. This work may inform the design of anti-HIV-1 DNA helix-based inhibitors with new structures or mechanisms.