Soloxolone methyl inhibits influenza virus replication and reduces virus-induced lung inflammation

Abstract

Highly pathogenic influenza viruses pose a serious public health threat to humans. Although vaccines are available, new antivirals are needed to efficiently control disease progression and virus transmission due to the emergence of drug-resistant viral strains. In this study, we describe the anti-viral properties of Soloxolone methyl (SM) (methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate, a chemical derivative of glycyrrhetinic acid) against the flu virus. Anti-flu efficacy studies revealed that SM exhibits antiviral activity against the H1N1 influenza A virus in a dose-dependent manner causing a more than 10-fold decrease in virus titer and a reduction in the expression of NP and M2 viral proteins. In a time-of-addition study, SM was found to act at an early stage of infection to exhibit an inhibitory effect on both the attachment step and virus uptake into cells. Also, in infected cells SM downregulates the expression of the inflammatory cytokines IL-6 and TNF-α. In infected mice, SM administered intranasally prior to and after infection significantly decreases virus titers in the lung and prevents post-challenge pneumonia. Together, these results suggest that Soloxolone methyl might serve as an effective therapeutic agent to manage influenza outbreaks and virus-associated complications, and further preclinical and clinical investigation may be warranted.

Dual Effect of Soloxolone Methyl on LPS-Induced Inflammation In Vitro and In Vivo

“…Earlier, we showed that SM exhibited anti-inflammatory activity in animal models with primary local inflammation, such as influenza virus A-induced pneumonia [ 55 ], as well as carrageenan and histamine-induced paw oedema [ 73 ]. Here, the anti-inflammatory effect of SM was studied in vivo using models of LPS-induced endotoxemia and carrageenan-induced peritonitis, both of which are models of acute inflammation, but with different triggers and mechanisms.…”

“…In addition, we showed that SM displays anti-inflammatory activity; SM caused a significant and dose-dependent decrease in NO production in LPS-activated J774 murine macrophages [ 54 ]. Moreover, we showed that SM inhibits the influenza virus A-activated expression of IL-6 and TNF-α and prevents the development of inflammatory changes in lung tissue caused by the virus in mice [ 55 ].…”

Trioxolone Methyl, a Novel Cyano Enone-Bearing 18βH-Glycyrrhetinic Acid Derivative, Ameliorates Dextran Sulphate Sodium-Induced Colitis in Mice

“…The structure of TM was further confirmed by 1 H and 13 C-NMR and high-resolution mass spectrometry. Given the revealed ability of SM to suppress the inflammatory response of lipopolysaccharide (LPS)-stimulated J774 macrophages in vitro [16] and carrageenan-induced acute paw edema and influenza A-associated pneumonia in murine models [15,17], we questioned whether the formation of an additional enone moiety in rings D/E along with the enone system in ring C increased the antiinflammatory properties of the molecule in vitro and in vivo. Here, we showed that TM effectively suppressed NO production by LPS-challenged J774 macrophages in vitro and dextran sulfate sodium (DSS)-induced colitis in mice in vivo.…”

“…The modification of natural materials by this group was shown to significantly Previously, our research group synthesized and evaluated the bioactivities of soloxolone methyl (SM), a position isomer of bardoxolone methyl based on a 18βH-glycyrrhetinic acid scaffold [10]. We showed that SM effectively inhibited tumor cell growth in vitro [10] and in vivo [15] and displayed marked anti-inflammatory and anti-influenza A activities [15][16][17]. In our previous report, structureactivity relationship (SAR) analysis revealed that the acceptor center at C-9 in ring C was crucial for the bioactivity of SM-an analog of SM with a saturated 9(11)-double bond was found to display a significantly lower cytotoxicity and a significantly lower inhibitory effect on nitric oxide (II) (NO) production by inflamed macrophages compared to SM [16].…”

Structure – Anti-influenza Type a Activity Relationship among a Series of Nitrogen Lupane Triterpenoids

“…Lupane 2,3-secoderivatives are able to suppress the reproduction of HSV-1 and Flu A (EC 50 from 1.9 to 21.3 µM) [13]. 2-Cyano-glycyrrhetic acid exhibits Flu A H1N1 antiviral activity causing a more than 10-fold decrease in virus titer [14]. Glycyrrhizic acid conjugates with aminoacids show activity against Flu A (H3N2, H1N1, H5N1, SI ranged from 10 to 29), and HRSV (SI 25) [15].…”