Synthesis, Biophysical Characterization, and Anti-HIV-1 Fusion Activity of DNA Quadruplex-based Inhibitors with Dipeptide MT Hook Conjugation

Author(s): Liang Xu*, Zeye Han, Hongqian Ren

Journal Name: Current HIV Research
HIV and Viral Immune Diseases

Volume 19 , Issue 4 , 2021

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Graphical Abstract:


Background: Human immunodeficiency virus type-1 (HIV-1) infection is the reason for the epidemic of acquired immunodeficiency syndrome (AIDS). The development of HIV-1 fusion inhibitors has gained increasing attention as they were found to be effective in the early stage of HIV-1. DNA G-quadruplex-based inhibitors have been found to interact with HIV-1 envelope glycoprotein, showing anti–HIV-1 fusion activity. C-peptide-derived molecules with Met-Thr terminal also showed potent anti-fusion activity; the Met-Thr dipeptide adopted a hook-like structure (termed MT hook) in the hydrophobic pocket to “anchor” inhibitors to the N-terminal heptad repeat (NHR) of HIV-1 envelope glycoprotein gp41.

Objective: Our work was aimed to conjugate MT hooks to the 5'-terminal ends of DNA quadruplex- based inhibitor and demonstrate its biophysical characterization and anti–HIV-1 fusion activity.

Methods: A 6-aminohexanol phosphonamidite was utilized in solid synthesis for the conjunction of oligodeoxynucleotide and MT dipeptide. Hydrophobic groups were introduced by a nucleoside analogue from the base site. Circular dichroism spectrum and native polyacrylamide gel electrophoresis were used to confirm the helix formation. A cell-cell fusion assay was carried out to test the anti-fusion activity.

Results: The conjugate G1 showed improved anti-cell-cell fusion activity than quadruplex without MT hook. The MT hook did not affect the oligodeoxynucleotide (ODN) G-quadruplex assembly. It was also proved that G1 could effectively interfere with endogenous 6-helical bundle (6HB) formation between the N-terminal heptad repeat N36 (NHR) and the C-terminal heptad repeat C34 (CHR) during virus fusion course.

Conclusion: In this work, a conjugate of DNA-oligopeptide was successfully synthesized. The conjugation of MT hook did improve the anti-fusion activity of DNA G-quadruplex-based inhibitors. Our results can provide information regarding structure-activity relationships of DNA helix-based inhibitors and a reference for the follow-up experimental studies.

Keywords: Oligodeoxynucleotide, quadruplex, MT hook, conjugate, HIV-1, fusion inhibitor.

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Article Details

Year: 2021
Published on: 23 April, 2021
Page: [317 - 323]
Pages: 7
DOI: 10.2174/1570162X19666210423121601
Price: $65

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PDF: 273