title: TACE antagonists blocking ACE2 shedding caused by the spike protein of SARS-CoV are candidate antiviral compounds.
abstract: Because outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) might reemerge, identifying antiviral compounds is of key importance. Previously, we showed that the cellular factor TNF-alpha converting enzyme (TACE), activated by the spike protein of SARS-CoV (SARS-S protein), was positively involved in viral entry, implying that TACE is a possible target for developing antiviral compounds. To demonstrate this possibility, we here tested the effects of TACE inhibitors on viral entry. In vitro and in vivo data revealed that the TACE inhibitor TAPI-2 attenuated entry of both pseudotyped virus expressing the SARS-S protein in a lentiviral vector backbone and infectious SARS-CoV. TAPI-2 blocked both the SARS-S protein-induced shedding of angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV, and TNF-alpha production in lung tissues. Since the downregulation of ACE2 by SARS-S protein was proposed as an etiological event in the severe clinical manifestations, our data suggest that TACE antagonists block SARS-CoV infection and also attenuate its severe clinical outcome.
authors.affiliation: Department of Intractable Diseases, International Medical Center of Japan, 1-21-1 Toyama, Tokyo, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Haga
authors.forename: Noriyo
authors.initials: N
authors.lastname: Nagata
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Sata
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishizaka
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000072198:ADAM17 Protein; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008168:Lung / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000472:pathogenicity*; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000502:physiology*; D053586:Virus Internalization
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D064370:Spike Glycoprotein, Coronavirus; C099410:TAPI-2; D014759:Viral Envelope Proteins; C578557:spike glycoprotein, SARS-CoV; C578553:spike protein, mouse hepatitis virus; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse