Edited by Hans-Dieter KlenkKeywords: Hepatitis C virus (HCV) core protein Yeast growth defect caused by core protein HSP90 inhibitor Stability nascent polypeptide HSC90 High-throughput screening a b s t r a c t Hepatitis C virus core protein (Core) contributes to HCV pathogenicity. Here, we demonstrate that Core impairs growth in budding yeast. We identify HSP90 inhibitors as compounds that reduce intracellular Core protein level and restore yeast growth. Our results suggest that HSC90 (Hsc82) may function in the protection of the nascent Core polypeptide against degradation in yeast and the C-terminal region of Core corresponding to the organelle-interaction domain was responsible for Hsc82-dependent stability. The yeast system may be utilized to select compounds that can direct the C-terminal region to reduce the stability of Core protein.