Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus.
The discovery and development of new, highly potent anti-coronavirus agents and effective approaches for controlling the potential emergence of epidemic coronaviruses still remains an important mission. Here, we identified tylophorine compounds, including naturally occurring and synthetic phenanthroindolizidines and phenanthroquinolizidines, as potent in vitro inhibitors of enteropathogenic coronavirus transmissible gastroenteritis virus (TGEV). The potent compounds showed 50% maximal effective concentration (EC₅₀) values ranging from 8 to 1468 nM as determined by immunofluorescent assay of the expression of TGEV N and S proteins and by real time-quantitative PCR analysis of viral yields. Furthermore, the potent tylophorine compounds exerted profound anti-TGEV replication activity and thereby blocked the TGEV-induced apoptosis and subsequent cytopathic effect in ST cells. Analysis of the structure-activity relations indicated that the most active tylophorine analogues were compounds with a hydroxyl group at the C14 position of the indolizidine moiety or at the C3 position of the phenanthrene moiety and that the quinolizidine counterparts were more potent than indolizidines. In addition, tylophorine compounds strongly reduced cytopathic effect in Vero 76 cells induced by human severe acute respiratory syndrome coronavirus (SARS CoV), with EC₅₀ values ranging from less than 5 to 340 nM. Moreover, a pharmacokinetic study demonstrated high and comparable oral bioavailabilities of 7-methoxycryptopleurine (52.7%) and the naturally occurring tylophorine (65.7%) in rats. Thus, our results suggest that tylophorine compounds are novel and potent anti-coronavirus agents that may be developed into therapeutic agents for treating TGEV or SARS CoV infection.
Yang
Cheng-Wei
CW
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC.
Lee
Yue-Zhi
YZ
Kang
Iou-Jiun
IJ
Barnard
Dale L
DL
Jan
Jia-Tsrong
JT
Lin
Du
D
Huang
Chun-Wei
CW
Yeh
Teng-Kuang
TK
Chao
Yu-Sheng
YS
Lee
Shiow-Ju
SJ
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D029062:Apocynaceae / Q000378:metabolism; D002522:Chlorocebus aethiops; D018352:Coronavirus Infections / Q000188:drug therapy; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005761:Gastroenteritis, Transmissible, of Swine / Q000821:virology; D007212:Indolizines / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D010616:Phenanthrenes / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D011807:Quinolizines / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D045169:Severe Acute Respiratory Syndrome / Q000821:virology; D013329:Structure-Activity Relationship; D013552:Swine; D005760:Transmissible gastroenteritis virus / Q000187:drug effects*; D031110:Tylophora; D014709:Vero Cells
C518787:7-methoxycryptopleurine; D000470:Alkaloids; D000998:Antiviral Agents; D007212:Indolizines; D010616:Phenanthrenes; D010618:Phenanthrolines; D011807:Quinolizines; C521640:phenanthroindolizidine; C521641:phenanthroquinolizidine; C004218:tylophorine