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The host-targeting compound peruvoside has a broad-spectrum antiviral activity against positive-sense RNA viruses

Acta Pharmaceutica Sinica B 2023年第5期13卷 2039-2055页

作者： Kan Xing Wu Thinesshwary Yogarajah marcus wing choy loe Parveen Kaur Regina Ching Hua Lee Chee Keng Mok Yi Hao Wong Patchara Phuektes Li Sze Yeo Vincent T.K.Chow Yong Wah Tan Justin Jang Hann Chu Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University Health SystemNational University of SingaporeSingapore 117597Singapore Department of Pathobiology Faculty of Veterinary MedicineKhonkaen UniversityKhonkaen 40002Thailand Infectious Disease Programme Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117597Singapore Institute of Molecular and Cell Biology Agency for ScienceTechnology and Research(A∗STAR)Singapore 138648Singapore Lee Kong Chian School of Medicine Nanyang Technological UniversitySingapore 308232Singapore NUSMed Biosafety Level 3 Core Facility Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117599Singapore

Positive-sense RNA viruses modify intracellular calcium stores,endoplasmic reticulum and Golgi apparatus(Golgi)to generate membranous replication organelles known as viral factories.Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity.Here,we identified the vital role of a broadspectrum antiviral,peruvoside in limiting the formation of viral factories.Mechanistically,we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1(GBF1)phosphorylation and Golgi vesiculation by peruvoside treatment.The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation.Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337(T1337).We also showed 100%of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum.These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside,host-directed antivirals for positive-sense RNA virus-mediated disease,in the interim where no vaccine is available.

关键词： Positive-sense RNA viruses Peruvoside Antiviral CDKI signaling Viral factories Calcium efflux Broad-spectrum Golgi apparatus

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