Indomethacin has a potent antiviral activity against SARS coronavirus.
Severe acute respiratory syndrome (SARS) is a newly emerging, highly transmissible and fatal disease caused by a previously unknown coronavirus (SARS-CoV). Existing in non-identified animal reservoirs, SARS-CoV continues to represent a threat to humans because there is no effective specific antiviral therapy for coronavirus infections.


OBJECTIVE
Starting from the observation that cyclopentenone cyclooxygenase (COX) metabolites are active against several RNA viruses, we investigated the effect of the COX inhibitor indomethacin on coronavirus replication.


METHODS
Work involving infectious SARS-CoV was performed in biosafety level 3 facilities. SARS-CoV was grown in monkey VERO cells and human lung epithelial A549 cells, while canine coronavirus (CCoV) was grown in A72 canine cells. Antiviral activity was analysed by determining infective virus titres by TCID50, viral RNA synthesis by Northern blot analysis and real-time RT-PCR, and viral protein synthesis by SDS-PAGE analysis after 35S-methionine-labelling. Antiviral efficacy in vivo was determined by evaluating virus titres in CCoV-infected dogs treated orally with 1 mg/kg body weight indomethacin (INDO).


RESULTS
Unexpectedly, we found that INDO has a potent direct antiviral activity against the coronaviruses SARS-CoV and CCoV. INDO does not affect coronavirus binding or entry into host cells, but acts by blocking viral RNA synthesis at cytoprotective doses. This effect is independent of cyclooxygenase inhibition. INDO's potent antiviral activity (>1,000-fold reduction in virus yield) was confirmed in vivo in CCoV-infected dogs.


CONCLUSIONS
The results identify INDO as a potent inhibitor of coronavirus replication and suggest that, having both anti-inflammatory and antiviral activity, INDO could be beneficial in SARS therapy.
Amici
Carla
C
Department of Biology, University of Rome Tor Vergata, Rome, Italy.
Di Caro
Antonino
A
Ciucci
Alessandra
A
Chiappa
Lucia
L
Castilletti
Concetta
C
Martella
Vito
V
Decaro
Nicola
N
Buonavoglia
Canio
C
Capobianchi
Maria R
MR
Santoro
M Gabriella
MG
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D018352:Coronavirus Infections / Q000188:drug therapy / Q000662:veterinary; D017939:Coronavirus, Canine / Q000187:drug effects; D004283:Dog Diseases / Q000188:drug therapy; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000821:virology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology* / Q000627:therapeutic use; D016898:Interferon-alpha / Q000494:pharmacology; D012367:RNA, Viral / Q000302:isolation & purification; D012254:Ribavirin / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin; D001241:Aspirin; D007213:Indomethacin