📄 Implication of proprotein convertases in the processing and spread of severe acute respiratory syndrome coronavirus

Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of SARS. Analysis of SARS-CoV spike glycoprotein (S) using recombinant plasmid and virus infections demonstrated that the S-precursor (proS) exists as a ∼190 kDa endoplasmic reticulum form and a ∼210 kDa Golgi-modified form. ProS is subsequently processed into two C-terminal proteins of ∼110 and ∼80 kDa. The membrane-bound proprotein convertases (PCs) furin, PC7 or PC5B enhanced the production of the ∼80 kDa protein. In agreement, proS processing, cytopathic effects, and viral titers were enhanced in recombinant Vero E6 cells overexpressing furin, PC7 or PC5B. The convertase inhibitor dec-RVKR-cmk significantly reduced proS cleavage and viral titers of SARS-CoV infected cells. In addition, inhibition of processing by dec-RVKR-cmk completely abrogated the virus-induced cellular cytopathicity. A fluorogenically quenched synthetic peptide encompassing Arg 761 of the spike glycoprotein was efficiently cleaved by furin and the cleavage was inhibited by EDTA and dec-RVKR-cmk. Taken together, our data indicate that furin or PC-mediated processing plays a critical role in SARS-CoV spread and cytopathicity, and inhibitors of the PCs represent potential therapeutic anti-SARS-CoV agents. © 2004 Elsevier Inc.

keywords 🔗 syndrome coronavirus (1074) 🔗 cytopathic effect (91) 🔗 endoplasmic reticulum (78) 🔗 etiological agent (62) 🔗 spike glycoprotein (99) 🔗 infected cells (307) 🔗 respiratory syndrome (2004) 🔗 acute respiratory (1734)

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