Abstract
Tylophorine analogs have been shown to exhibit diverse activities against cancer, inflammation, arthritis, and lupus in vivo. In this study, we demonstrated that two tylophorine analogs, DCB-3503 and rac-cryptopleurine, exhibit potent inhibitory activity against hepatitis C virus (HCV) replication in genotype 1b Con 1 isolate. The inhibition of HCV replication is at least partially mediated through cellular heat shock cognate protein 70 (Hsc70). Hsc70 associates with the HCV replication complex by primarily binding to the poly U/UC motifs in HCV RNA. The interaction of DCB-3503 and rac-cryptopleurine with Hsc70 promotes the ATP hydrolysis activity of Hsc70 in the presence of the 3′ poly U/UC motif of HCV RNA. Regulating the ATPase activity of Hsc70 may be one of the mechanisms by which tylophorine analogs inhibit HCV replication. This study demonstrates the novel anti-HCV activity of tylophorine analogs. Our results also highlight the importance of Hsc70 in HCV replication.
Highlights
Tylophorine analogs inhibit selected set of protein syntheses by inhibiting the elongation step[8]
While resistant clones emerged under the selection of a 10-fold EC50 concentration of meso-tetrakis-porphyrin compound 6 (200 nM), a potent hepatitis C virus (HCV) inhibitor developed in our laboratory that targeta viral protease (Figure S1a)[24]
The tylophorine analogs have exhibited various activities, yet the only molecular target VEGFR2 revealed for this group of compounds was associated with their anti-cancer activities[9]
Summary
Tylophorine analogs inhibit selected set of protein syntheses by inhibiting the elongation step[8] Both HCV replication and protein synthesis take place on the endoplasmic reticulum (ER). We demonstrated that DCB-3503 and rac-cryptopleurine potently inhibit HCV replication They both exhibit anti-HCV activity by promoting the ATP hydrolysis activity of Hsc[70] through binding to the 3′ poly U/UC motif of HCV RNA. This allosteric regulation of Hsc[70] function alters the interaction between Hsc[70] and its associated HCV protein and RNA, and perturbs the homeostasis of the HCV replication complex, inhibiting translation of HCV RNA
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