Seco -pregnane steroids target the subgenomic RNA of alphavirus-like RNA viruses

Abstract

Plants have evolved multiple mechanisms to selectively suppress pathogens by production of secondary metabolites with antimicrobial activities. Therefore, direct selections for antiviral compounds from plants can be used to identify new agents with potent antiviral activity but not toxic to hosts. Here, we provide evidence that a class of compounds, seco-pregnane steroid glaucogenin C and its monosugar-glycoside cynatratoside A of Strobilanthes cusia and three new pantasugar-glycosides of glaucogenin C of Cynanchum paniculatum, are effective and selective inhibitors to alphavirus-like positive-strand RNA viruses including plant-infecting tobacco mosaic virus (TMV) and animal-infecting Sindbis virus (SINV), eastern equine encephalitis virus, and Getah virus, but not to other RNA or DNA viruses, yet they were not toxic to host cells. In vivo administration of the compounds protected BALB/c mice from lethal SINV infection without adverse effects on the mice. Using TMV and SINV as models, studies on the action mechanism revealed that the compounds predominantly suppress the expression of viral subgenomic RNA(s) without affecting the accumulation of viral genomic RNA. Our work suggested that the viral subgenomic RNA could be a new target for the discovery of antiviral drugs, and that seco-pregnane steroid and its four glycosides found in the two medicinal herbs have the potential for further development as antiviral agents against alphavirus-like positive-strand RNA viruses.antiviral drugs ͉ Strobilanthes cusia ͉ Cynanchum atratum V iruses replicate in host cells by hijacking the host-cell metabolic machinery. It is therefore difficult for antiviral therapies to inhibit only viral functions but spare host cellular processes. Nevertheless, great progress has been achieved over the past decades in antiviral research and therapy to reduce morbidity and mortality in virus-infected individuals (1, 2), and many antiviral drugs have been approved in recent years, most of which targeted either viral proteins or host cellular proteins. However, some of these compounds might induce the resistance of viruses to them and cause cell toxicity (3-5). The continuing emergence of highly pathogenic viruses like avian influenza viruses and severe acute respiratory syndrome coronavirus underscores the importance of advancing the search for effective antiviral agents. Plants have evolved constitutive and inducible defense mechanisms by producing a vast array of secondary metabolites against various microbial pathogens (6). Many herbaceous plants have been used in traditional Chinese medicine to treat viral diseases (7). It is conceivable that antiviral compounds would occur in plants as part of their innate defense arsenal, and the vast assortment of secondary metabolites could serve as a large pool for screening for previously undescribed antiviral compounds with a selective target spectrum and nontoxic to the host plants. Here, we provide evidence that a class of compounds, the seco-pregnane steroid and its glycosides from Strobilanthe...

Novel Indole-2-Carboxamide Compounds Are Potent Broad-Spectrum Antivirals Active against Western Equine Encephalitis Virus In Vivo

“…Numerous compounds have been shown to suppress alphavirus replication in cultured cells, but only a few have shown any activity in animal models (13)(14)(15)(16)(17). We demonstrate that CCG205432 and CCG209023 reduce clinical disease and improve survival in mice given a lethal challenge of WEEV.…”

“…Furthermore, the combination of active vaccination plus antiviral therapy may be a more effective response in the setting of an outbreak caused either by natural transmission or by intentional exposure to one of these viral pathogens (12). Although numerous compounds have been reported to inhibit alphavirus replication in cultured cells, only a select few have shown any activity in animal models (13)(14)(15)(16)(17). Thus, there is a pressing need to identify new antiviral compounds and drug targets as part of a comprehensive medical-countermeasure strategy to prevent or mitigate illness, suffering, and death resulting from infections caused by these virulent pathogens (18).…”

Immunosuppressive C21 steroidal glycosides from the root of Cynanchum atratum

“…As a kind of characteristic and bioactive constituents, more than 200 C 21 steroidal glycosides have been isolated from Cynanchum species [7] and at least 50 ones have been found from C. atratum [3,4,6,8,9]. Previous researches revealed that C 21 steroids have anti-tumor, immunosuppressive, antidepressant, neuroprotective, antivirus, and appetite-suppressing activities [10][11][12][13][14][15]. Of them, the immune suppressive activity is one of research focuses owing to the significant effects presented by most C 21 steroidal glycosides [11,16].…”

Neuroprotective polyhydroxypregnane glycosides from Cynanchum otophyllum

“…Previous chemical investigations of this species have resulted in the isolation of a number of pregnane glucosides with the structural variations usually occurring on the substitutions at C-3 and C-12 of the pregnane core [2][3][4][5]. Recently, pregnane glycosides have attracted considerable attention for their broad range of bioactivities, such as anti-epileptic activity [6], multidrug-resistance modulating activity [7], immunological activity [8], and antiviral properties [9]. In our continuing search for structurally and biologically interesting metabolites from medical plant resources [10][11][12], five new pregnane glycosides together with two known steroids ( Fig.…”