Structure-activity relationships of cryptopleurine analogs with E-ring modifications as anti-hepatitis C virus agents |
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Authors: | Ying Wang Shao-Ru Chen Xiaoming Yang Kuo-Hsiung Lee Yung-Chi Cheng |
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Affiliation: | 1. Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States;2. Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau;3. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States;4. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan |
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Abstract: | The tylophorine analog rac-cryptopleurine exhibited potent anti-hepatitis C virus (HCV) activity through allosteric regulation of ATPase activity of heat shock cognate protein 70 (Hsc70). We evaluated the impact of modifications on the E-ring of rac-cryptopleurine to the inhibitory activity against HCV replication and regulation of ATPase activity of Hsc70. Cryptopleurine analog YXM-110 with a 13α-hydroxyl group maintained activity against HCV and promoted ATP/ADP turnover of Hsc70; however, compounds with hydroxyl groups at other positions or with other orientations (YXM-109, YXM-139, and YXM-140) did not exhibit similar activities. Size modification or heteroatom incorporation of the E-ring led to loss of anti-HCV activity. Promotion of the chaperone activity of Hsc70 with carboxyl terminus Hsc70 interacting protein (CHIP) further enhanced the anti-HCV activity of rac-cryptopleurine and XYM-110. This structure-activity relationship (SAR) study refined structural design and optimization for developing rac-crytopleurine analogs as potent anti-HCV agents targeted against the host factor involved in HCV replication. |
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Keywords: | Corresponding authors at: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States (Y.-C. Cheng) Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States (K.-H. Lee). |
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