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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 and Hongqian Ren  

Abstract:


Background: Human immunodeficiency virus type-1 (HIV-1) infection is the reason for the epidemic of acquired immunodeficiency syndrome (AIDS). Developing HIV-1 fusion inhibitors gained increasing attention as they took effect in the early stage of HIV-1 infecting cells. DNA G-quadruplex-based inhibitors had 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 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, conjugate of DNA-oligopeptide were successfully synthesized. The conjugation of MT hook did improve the anti-fusion activity of DNA G-quadruplex-based inhibitors. Our results can add information regarding on structure-activity relationships of DNA helix-based inhibitors and provide a reference for the follow-up experimental studies.

Keywords:

Oligodeoxynucleotide, quadruplex, MT hook, conjugate, HIV-1, fusion inhibitor

Affiliation:

State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing



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