Evaluating the Effect of Amine-geldanamycin Hybrids on Antiviral Activity against Influenza Virus

Abstract

Aims: The purpose of this study was to synthesis novel amine-geldanamycin hybrids (AGH) and evaluate their biological properties.
 Study Design: Experimental study.
 Place and Duration of Study: The study was carried out at the Department of Microbiology and Department of Chemistry, Faculty of Science, Silpakorn University, from December 2019 - November 2020.
 Methodology: Three new amine-geldanamycin hybrids (AGH); compounds 2 to 4 were synthesised by nucleophilic substitution of geldanamycin (1). The solubility, cytotoxicity, antiviral activity and molecular docking analyses were carried out.
 Results: The solubility of AGH in water was 1.918-5.571 mM, higher than that of compound 1. Compound 2 exhibited weak cytotoxicity activity against Vero and LLC-MK2 cells, with IC50 values of 229.19 and 330.58 µg/ml, respectively. All compounds inhibited influenza virus propagation in embryonated chicken eggs at the lowest amount of 1.25 µg per egg. They interacted positively with Hsp90, showing a binding free energy (DG) of -112.00 to -116.34 kcal/mol, which indicated lower Hsp90 affinity compared with that of geldanamycin (-133.06 kcal/mol) and 17-dimethylamino ethylamino-17-demethoxygeldanamycin (-136.55 kcal/mol), despite being bound in the similar active site. For the viral absorption, only AGH inhibited hemagglutination at a concentration of 25 µg/ml.
 Conclusion: The study findings revealed, through molecular docking analysis, that the development of AGH improved the antiviral activity. The AGH inhibited not only influenza virus propagation, but also viral absorption. Therefore, AGH could be considered a new choice for antiviral agents.

Geldanamycin ameliorates multiple organ dysfunction and microthrombosis in septic mice by inhibiting the formation of the neutrophil extracellular network by activating heat shock factor 1 HSF1

“…Geldanamycin was first found to have antiprotozoal and antitumor effects by Sasaki et al 27 Later, good antiviral activity of GA was also found 28 . Various activities of GA, such as immune regulation 29 and oxidation, 30 were also revealed.…”

“…[24][25][26] Therefore, in this study, we investigated the effects of GA on multiple organ Geldanamycin was first found to have antiprotozoal and antitumor effects by Sasaki et al 27 Later, good antiviral activity of GA was also found. 28 Various activities of GA, such as immune regulation 29 and oxidation, 30 were also revealed. Past studies have shown that GA reduced protein stability and promoted its degradation by specifically binding to HSP90, one of the most active chaperones in the cell, thereby inhibiting tumour cell growth signalling pathways.…”