Antiviral evaluation of an Hsp90 inhibitor, gedunin, against dengue virus

Deeba Amraiz,Najam-Us-Sahar Sadaf Zaidi,Munazza Fatima

doi:10.4314/tjpr.v16i5.5

Abstract

Purpose: To evaluate the antiviral potential of a tetranortriterpenoid, gedunin, against dengue virus (DENV) replication by targeting the host chaperone, Hsp90.Methods: The compound, gedunin, was tested against the replication of DENV in vitro using BHK-15 cells transfected with DENV-2 subgenomic replicon. Molecular docking of gedunin with Hsp90 protein was performed for evaluation of mode of action, using the program, Autodock vina.Results: In vitro antiviral data showed that gedunin significantly (p < 0.05) reduced DENV replication with EC50 of 10 μM. Further, in silico molecular docking data revealed strong interaction of gedunin with the ATP/ADP binding site of the host protein, Hsp90, with an estimated average free binding energy of -8.9 kcal/mol.Conclusion: The results validate gedunin as a potential antiviral candidate. Further in vitro assays and in vivo viral challenge studies are required to confirm the exact mode of action and pharmacological profile of gedunin in DENV infections.Keywords: Dengue virus replication, Hsp90, Gedunin, Antiviral, Molecular docking

Highlights

Dengue virus belongs to the family Flaviviridae and has recently emerged as a significant human pathogen causing 50-100 million infections per year globally [1]
It was shown that gedunin as an anticancer agent inhibits the function of Hsp90 protein, resulting in the degradation and improper functioning of the client proteins, similar to other Hsp90 inhibitors [8]
Geldanamycin was shown to be active against replication of a range of viruses, including herpes simplex virus type 1 (HSV-1), severe acute respiratory syndrome coronavirus and Zaire EBOV in vitro [10,11]

Summary

Introduction

Dengue virus belongs to the family Flaviviridae and has recently emerged as a significant human pathogen causing 50-100 million infections per year globally [1]. Several studies have previously suggested that both viral and host proteins essential for viral replication can be exploited for antiviral development [1]. Hsp is an ATP dependent heat shock protein, which is highly conserved among many species from yeast to humans and involved in the regulation of several signaling, oncogenic and cell cycle protein [4,5]. It was shown that gedunin as an anticancer agent inhibits the function of Hsp protein, resulting in the degradation and improper functioning of the client proteins, similar to other Hsp inhibitors [8]. Numerous Hsp inhibitors, identified as anticancer agents such as radicicol, geldanamycin (GA), and GA derivatives, block Hsp activity by binding to the N-terminal ATP pocket of the protein and inhibiting ATPase activity [9]. Geldanamycin was shown to be active against replication of a range of viruses, including herpes simplex virus type 1 (HSV-1), severe acute respiratory syndrome coronavirus and Zaire EBOV in vitro [10,11]

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