Antiviral activity of coxsackievirus B3 3C protease inhibitor in experimental murine myocarditis.
BACKGROUND
We investigated the efficacy of a 3C protease inhibitor (3CPI) in a murine coxsackievirus B3 (CVB3) myocarditis model. CVB3 is a primary cause of viral myocarditis. The CVB3 genome encodes a single polyprotein that undergoes a series of proteolytic events to produce several viral proteins. Most of this proteolysis is catalyzed by the 3C protease (3CP).


RESULTS
By way of a micro-osmotic pump, each mouse received 50 mM 3CPI in 100 μL of 100% dimethyl sulfoxide (DMSO) during a 72-hour period. On the day of pump implantation, mice (n = 40) were infected intraperitoneally with 10(6) plaque-forming units of CVB3. For the infected controls (n = 50), the pump was filled with 100% DMSO without 3CPI. The 3-week survival rate of 3CPI-treated mice was significantly higher than that of controls (90% vs 22%; P < .01). Myocardial inflammation, viral titers, and viral RNA levels were also reduced significantly in the 3CPI-treated group compared with these measures in the controls.


CONCLUSIONS
The protein-based drug 3CPI inhibited the activity of 3CP of CVB3, significantly inhibited viral proliferation, and attenuated myocardial inflammations, subsequent fibrosis, and CVB3-induced mortality in vivo. Thus, this CVB3 3CPI has the potential to be a novel therapeutic agent for the treatment of acute viral myocarditis during the viremic phase.
Division of Cardiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
Soo-Hyeon
SH
Yun
Won Gil
WG
Lee
Yong-Chul
YC
Kim
Eun-Seon
ES
Ju
Byung-Kwan
BK
Lim
Jin-Oh
JO
Choi
Duk-Kyung
DK
Kim
Eun-Seok
ES
Jeon
D000086042:3C Viral Proteases; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D003546:Cysteine Endopeptidases; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006321:Heart / Q000821:virology; D006651:Histocytochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008853:Microscopy; D009205:Myocarditis / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D009206:Myocardium / Q000473:pathology; D010179:Pancreas / Q000821:virology; D016019:Survival Analysis; D019562:Viral Load; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases