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Antiviral Activity of Geldanamycin and Its Derivatives Against Influenza Virus

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Antiviral Activity of Geldanamycin and Its Derivatives Against Influenza Virus Journal of Applied Pharmaceutical Science Vol. 10(04), pp 113-120, April, 2020 Available online at http://www.japsonline.com DOI: 10.7324/JAPS.2020.104014 ISSN 2231-3354 Antiviral activity of geldanamycin and its derivatives against influenza virus Thongchai Taechowisan1*, Tipparat Samsawat1, Winyou Puckdee1, Waya S. Phutdhawong2 1Department of Microbiology, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand. 2Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand. ARTICLE INFO ABSTRACT Received on: 28/10/2019 Two new geldanamycin derivatives such as 17-(tryptamine)-17-demethoxygeldanamycin (2) and Accepted on: 15/02/2020 17-(5′-methoxytryptamine)-17-demethoxygeldanamycin (3) were synthesized by nucleophilic substitution of the Available online: 04/04/2020 C17 methoxyl of geldanamycin (1). Their antiviral activity was evaluated based on influenza virus propagation in embryonated chicken eggs and viral absorption by hemagglutination (HA) inhibition test. The findings indicated that these compounds inhibited viral propagation at a concentration of 12.5 µg/ml. For the viral absorption, only Key words: compounds 2 and 3 inhibited HA at a concentration of 50 µg/ml. The solubility of compounds 2 and 3 in water Antiviral activity, endophytic was 290 and 306 µM, higher than that of compound 1 about 1.91 and 2.01 times, respectively. The compounds 2 actinomycetes, geldanamycin, and 3 showed a moderate cytotoxic activity on LLC-MK2 and Vero cells with IC values of >200.00 µg/ml. These influenza virus, tryptamine- 50 results demonstrated the invention of tryptamine-geldanamycin hybrids to prevent influenza virus infection in viral geldanamycin hybrids. absorption and viral propagation steps. INTRODUCTION geldanamycin blocks the replication of the viruses both in vitro Geldanamycin is a benzoquinone ansamycin, and it and in vivo via inhibition of Hsp90 (Amraiz et al., 2017; Li et al., binds specifically to heat shock protein 90 (Hsp90) Prodromou( 2004; 2010; 2012; Luo et al., 2003; Schang et al., 2002; Smith et al., 1997; Sullivan et al., 1997), resulting in dysfunction and rapid et al., 2010; Wang et al., 2017). However, the therapeutic degradation of Hsp90-associated client proteins (Blagosklonny, utilization of this compound has been restricted by low water 2002; Richter and Buckner, 2001). As a specific inhibitor of Hsp90 solubility, metabolic instability, and severe hepatotoxicity (Fukuyo function, its derivatives showed antitumor activity (Miyata, 2005; et al., 2009; Supko et al., 1995). Therefore, its derivatives with Ochel et al., 2001) and has been used for the treatment of various improved pharmacokinetic profiles have been developed. The cancers (Biamonte et al., 2010; Jhaveri et al., 2012; Pacey et al., synthesized series of geldanamycin derivatives to make new types 2006). Intervention with the Hsp90 function is the mode of action of Hsp90 inhibitor with weak toxicity and high efficiency have of geldanamycin (Roe et al., 1999). been seeking (Kitson et al., 2013; Li et al., 2010; Lin et al., 2015; For viral replications, Hsp90 is necessary for the viral Modi et al., 2011; Shan et al., 2011; Supko et al., 1995; Tian et al., protein synthesis (Burch and Weller, 2005; Basha et al., 2005; 2004; Wrona et al., 2010). Connor et al., 2007; Geller et al., 2007; Hu and Seeger, 1996; Hu Tryptamine was the product of the decarboxylation et al., 1997; Hung et al., 2002; Li et al., 2004; Smith et al., 2010; of tryptophan. It has been used in the past as a vasodilator, Shan et al., 2011; Waxman et al., 2001). It has been shown that neurotransmitter, antiviral, antibacterial, antifungal, anti-inflammatory, and antioxidant agent Kousara( et al., 2017). Its modification has been conducted to be pharmacologically active compounds. Recently, tryptamine has been synthesized as a novel *Corresponding Author non nucleosidic compound against hepatitis B virus (Qu et al., 2011). Thongchai Taechowisan, Department of Microbiology, Faculty of Science, It has been a useful tool for improving the solubility, biological Silpakorn University, Nakhon Pathom 73000, Thailand. activities, and pharmacological properties of numerous natural E-mail: tewson84 @ hotmail.com © 2020 Thongchai Taechowisan et al. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). 114 Taechowisan et al. / Journal of Applied Pharmaceutical Science 10 (04); 2020: 113-120 products (Kousara et al., 2017). According to these effects, the substances (Taechowisan et al., 2019). This isolate was selected invention of tryptamine-geldanamycin hybrids has been designed. and identified using a polyphasic approach Taechowisan( and The C17 methoxyl group of geldanamycin molecule can permit for Lumyong, 2003; Taechowisan et al., 2019). The strain was cultured various nucleophiles to be introduced. Thus, geldanamycin has been a on ISP-2 agar plates at 30°C for 14 days and then was extracted popular template for producing various types of bioactive compounds with ethyl acetate. The crude extract was fractionated using low- (Lin et al., 2015; Modi et al., 2011; Supko et al., 1995; Tian et al., to-high polar solvents (ethyl acetate in hexane) and purified on 2004; Wrona et al., 2010). Furthermore, the other report showed Thin Layer Chromatography (TLC) (Taechowisan et al., 2019). that some of the 17-substituted geldanamycin derivatives contained The purified compound was undertaken to investigate on Nuclear stronger activity against hepatitis B virus than geldanamycin with Magnetic Resonance (NMR) spectroscopy. The spectral data of higher LD50 values than that of geldanamycin (Li et al., 2010). It has this compound corresponded to be geldanamycin (C29H40N2O9) (1). been reported that influenza virus replication could be inhibited by interfering the Hsp90 function (Chase et al., 2008). However, the Synthesis and solubility of geldanamycin derivatives activity of geldanamycin and its derivatives against influenza virus Geldanamycin derivatives were synthesized from has been not reported. Therefore, geldanamycin could inhibit the geldanamycin (Fig. 1) as described earlier (Taechowisan et al. functions of viral proteins by interfering with the complex formation 2019). The solubility of the novel geldanamycins in water was of Hsp90 and viral proteins. Inhibition of Hsp90 activity also determined by comparing with geldanamycin. causes the inhibition of viral protein synthesis. Furthermore, it has been reported that geldanamycin could inhibit viral replication by Viral strain propagation preventing the chaperone-mediated process in viral protein folding Influenza viruses A/free-grazing duck/Nakhon and functions (Li et al., 2004). Pathom/1/2017 (H5N2) (Taechowisan et al., 2018) were cultivated In this study, novel tryptamine-geldanamycin hybrids in embryonated eggs. Viral titer was determined using the HA were synthesized, their antiviral activity against influenza virus assay as previously described (Brauer and Chen, 2015). was evaluated based on virus propagation in embryonated chicken eggs and viral absorption by hemagglutination (HA) inhibition test, Virus cultivation inhibition assay and their water solubility and cytotoxicity were also determined. Virus cultivation inhibition assay was carried out by embryonated chicken egg inoculation. About 100 µl of tested MATERIALS AND METHODS compounds (12.5, 25, and 50 µg/ml) was incubated with 100 8 Isolation and cultivation of the actinomycete µl of seed virus (2.86 × 10 virus particles/ml) at 37°C for 30 minutes, and then, 100 µl of the mixture was inoculated into each Eighteen actinomycetes were isolated from the various embryonated chicken egg and incubated at 37°C for 4 days. The tissues (leaf, pseudostem, rhizome, and root) of Zingiber zerumbet allantoic fluid was harvested and then was tested by HA assay (L.) Smith (Taechowisan et al., 2017). Among the 18 isolates, the (Brauer and Chen, 2015). About 20 µg/ml of heparin (AppliChem, isolate W14 was found to be the best producer of antibacterial Germany) was used as a positive control. Figure 1. The semisynthetic route of 17-(tryptamine)-17-demethoxygeldanamycin (2) and 17-(5′-methoxytryptamine) -17-demethoxygeldanamycin (3) from geldanamycin (1). Taechowisan et al. / Journal of Applied Pharmaceutical Science 10 (04); 2020: 113-120 115 HA inhibition (HAI) assay atmosphere of 5% CO2. Cytotoxicity studies were performed on a HAI assay was used to evaluate the effect of the compounds 96-well plate. The cells were trypsinized and plated on a 96-well 5 in virus adsorption to target cells. The compounds (25 µl) with plate (2 × 10 per well) containing DMEM medium with 10% FBS two-fold serial dilution with Phosphate Buffered Saline (PBS) were and incubated overnight. Cells were incubated with the compounds mixed with an equal volume of seed influenza virus (400 HAU per at increasing concentrations in FBS-free medium for 24 hours. Cells 50 µl). After incubation at room temperature for 30 minutes, 50 were washed once, and 50 µl of FBS-free medium containing 5 mg/ µl of the solution was mixed with an equal volume of 1% chicken ml 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide erythrocyte suspension and then was incubated at 4°C for 30 minutes. (MTT) was added to each well and incubated in 5% CO2 at 37°C for The highest dilution of the compounds that prevented HA is called 4 hours. The medium was replaced with 50 µl of DMSO to
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