Identification of 23-( S )-2-Amino-3-Phenylpropanoyl-Silybin as an Antiviral Agent for Influenza A Virus Infection In Vitro and In Vivo

Abstract

It has been reported that autophagy is involved in the replication of many viruses. In this study, we screened 89 medicinal plants, using an assay based on the inhibition of the formation of the Atg12-Atg5/Atg16 heterotrimer, an important regulator of autophagy, and selected Silybum marianum L. for further study. An antiviral assay indicated that silybin (S0), the major active compound of S. marianum L., can inhibit influenza A virus (IAV) infection. We later synthesized 5 silybin derivatives (S1 through S5) and found that 23-(S)-2-amino-3-phenylpropanoyl-silybin (S3) had the best activity. When we compared the polarities of the substituent groups, we found that the hydrophobicity of the substituent groups was positively correlated with their activities. We further studied the mechanisms of action of these compounds and determined that S0 and S3 also inhibited both the formation of the Atg12-Atg5/Atg16 heterotrimer and the elevated autophagy induced by IAV infection. In addition, we found that S0 and S3 could inhibit several components induced by IAV infection, including oxidative stress, the activation of extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) and IB kinase (IKK) pathways, and the expression of autophagic genes, especially Atg7 and Atg3. All of these components have been reported to be related to the formation of the Atg12-Atg5/Atg16 heterotrimer, which might validate our screening strategy. Finally, we demonstrated that S3 can significantly reduce influenza virus replication and the associated mortality in infected mice. In conclusion, we identified 23-(S)-2-amino-3-phenylpropanoyl-silybin as a promising inhibitor of IAV infection.

Emodin Inhibition of Influenza A Virus Replication and Influenza Viral Pneumonia via the Nrf2, TLR4, p38/JNK and NF-kappaB Pathways

“…The viral titers of various supernatants were determined by plaque formation assay using MDCK cells as previously reported [ 43 , 44 ], the number of plaques (Ф > 1 mm) was counted. Plaque inhibition assay of test compounds was also performed as previously reported [ 45 ].…”

“…Primers are listed in Supplementary Materials Table S1 . The results were expressed as 2 −ΔΔCt [ 43 ].…”

Phytopharmaceuticals mediated Furin and TMPRSS2 receptor blocking: can it be a potential therapeutic option for Covid-19?

“…* can be projected for prevention of COVID Baicalein, Chrysin, Oro-xylin-A and its glycosides ( Lalou et al, 2013 ) Flavonoids and their glycosides Oroxylum indicum Furin Proprotein Convertase Furin inhibitor (Proprotein Convertase) Inhibit the tumor cell proliferation Celastrol (Shao et al ., 2015) Pentacyclic triterpeneof quinone methides. Tripterygium wilfordii, Celastrus regelii Prostate cancer TMPRSS2 inhibition followed by blocking of Androgen receptor Inhibition of prostate cancer growth * can be projected for COVID prevention Plant Lectin (Keyaerts et al ., 2015) Glycoprotein Allium sativum, Lycoris radiata Host cell ACE2 ACE2 binding of SARS-CoV-1 to inhibit the virus entry into host cells SARS-CoV-1 Ursolic acid (Chiang et al ., 2005) Pentacyclic triterpenoid Ocimum sanctum CD4 receptor Inhibit Protease, gp120-CD4 binding & entry; also immunomodulation against virus HIV, Coxa- kivirus B1, Enterovirus 71 (EV71) Acetyl-11-keto- boswellic acid (Von et al ., 2016 Pentacyclic terpenoid Boswellia serrata Specific host cell receptor in connection to virus entry, Able to block CHIKV at cell entry to Inhibit chikungunya and vesicular stomatitis virus (VSV) infections CHIKV, VSV May try for blocking interaction and attachment of SARS-COV-2 with host cell membrane Cepharanthine (Keyaerts et al ., 2013) Bisbenzyliso-quinoline Stephania cephalantha or other species Specific host cell receptor in connection to virus entry, not yet recruited Protease inhibitor, Antiinflammatory, antiviral immunomodulatory, anti-cancer Cancer, virus Might be used for novel Corona virus Sylimarin ( Dai et al ., 2013 ; Song et al ., 2011) Flavonoids Milk thistle ( Silybum marianum ) Specific host cell receptor in connection to virus entry, not yet recruited Viral RNA synthesis inhibitor and Influenza virus replication Anti-Influenza and Anti-CHKV ( Lani et al , 2015 ) and anti-Mayaro Virus activity ( Camini et al ...…”

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

“…have reported that silibin, the main component of silymarin, protected UVB-irradiated L929 cells from apoptotic death by repressing the activation of autophagy21. Besides, silibin could inhibit the activation of ERK/p38 MAPK pathways, subsequently decreasing the expression of autophagic genes in an influenza A virus infection model22. These evidences indicate that autophagy pathway might be a potential target of silymarin.…”