TY - JOUR
T1 - Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease
AU - Caballero-Camino, Francisco J.
AU - Rivilla, Ivan
AU - Herraez, Elisa
AU - Briz, Oscar
AU - Santos-Laso, Alvaro
AU - Izquierdo-Sanchez, Laura
AU - Lee-Law, Pui Y.
AU - Rodrigues, Pedro M.
AU - Munoz-Garrido, Patricia
AU - Jin, Sujeong
AU - Peixoto, Estanislao
AU - Richard, Seth
AU - Gradilone, Sergio A.
AU - Perugorria, Maria J.
AU - Esteller, Manel
AU - Bujanda, Luis
AU - Marin, Jose J.G.
AU - Banales, Jesus M.
AU - Cossío, Fernando P.
N1 - Publisher Copyright:
© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.
PY - 2021/1
Y1 - 2021/1
N2 - Background and Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.
AB - Background and Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.
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U2 - 10.1002/hep.31216
DO - 10.1002/hep.31216
M3 - Article
C2 - 32145077
AN - SCOPUS:85091311962
SN - 0270-9139
VL - 73
SP - 186
EP - 203
JO - Hepatology
JF - Hepatology
IS - 1
ER -
