Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease.

Abstract

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.

• Authors: Francisco J Caballero-Camino, Ivan Rivilla, Elisa Herraez, Oscar Briz, Alvaro Santos-Laso, Laura Izquierdo-Sanchez, Pui Y Lee-Law, Pedro M Rodrigues, Patricia Munoz-Garrido, Sujeong Jin, Estanislao Peixoto, Seth Richard, Sergio A Gradilone, Maria J Perugorria, Manel Esteller, Luis Bujanda, Jose J G Marin, Jesus M Banales, Fernando P Cossío
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 73 Issue 1 Pg. 186-203 (01 2021) ISSN: 1527-3350 [Electronic] United States
• PMID: 32145077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Bile Acids and Salts
• Synthetic Drugs
• Ursodeoxycholic Acid
• Histone Deacetylase 6

Topics

• Animals
• Apoptosis
• Bile Acids and Salts (metabolism)
• Bile Ducts (metabolism, pathology)
• Cell Proliferation (drug effects)
• Cysts (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Histone Deacetylase 6 (antagonists & inhibitors)
• Liver (drug effects, metabolism, pathology)
• Liver Diseases (drug therapy, metabolism, pathology)
• Random Allocation
• Rats
• Synthetic Drugs (pharmacology)
• Ursodeoxycholic Acid (pharmacology, therapeutic use)