Recent advances in S-adenosyl-L-homocysteine hydrolase inhibitors and their potential clinical applications

Abstract

S-Adenosyl-L-homocysteine (SAH) hydrolase is a ubiquitous cellular enzyme catalysing the hydrolysis of SAH to adenosine (Ado) and homocysteine (Hcy) in vivo. Due to its central role in regulation of biological methylation reactions, SAH hydrolase has been selected as a therapeutic target for a number of medical indications including antiviral, anticancer, anti-inflammation, immunosuppression and plasma Hcy-lowering for prevention or treatment of cardiovascular diseases. The current existing SAH hydrolase inhibitors can be divided into three types based on their mechanisms of enzyme inhibition. The most extensively studied SAH hydrolase inhibitors are Type I inhibitors that inactivate the enzyme in a pseudo-irreversible fashion. With our increased understanding of the biochemical properties and mechanisms of catalysis mediated by SAH hydrolase, the general trend in inhibitor design for SAH hydrolase has been to generate more potent and more specific inhibitors of the enzyme. Some of these inhibitors have been patented as antiviral agents and some as immunosuppressive agents. However, the number of patented SAH hydrolase inhibitors is very limited at the present time. The mechanism for antiviral efficacy is believed to be due to inhibition of viral mRNA methylation, and the mechanism for immunosuppressive efficacy is still not completely understood. Additional knowledge about the structure and the mechanism of catalysis of this enzyme as well as an understanding of the mechanism(s) of cytotoxicity related to enzyme inhibition, may allow for this enzyme to be used as a target for the design of drugs that control diseases ranging from carcinogenesis to viral infections, and from inflammation to atherosclerosis.

• adenosine analogues
• S-adenosyl-L-homocysteine hydrolase
• antiviral agents
• enzyme inhibitors
• immunosuppressive agents
• plasma homocysteine