Phosphodiesterases (PDEs) have the function of hydrolyzing intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading intracellular cAMP or cGMP, thereby terminating the transmission of these second messengers biochemical effects. cAMP and cGMP play an important regulatory role in cell activities. The regulation of its concentration is mainly determined by the balance between the synthesis of adenylyl cyclase and the hydrolysis of phosphodiesterases (PDEs). PDEs are widely distributed in the human body, and their physiological effects involve many research fields. In recent years, PDEs, as new therapeutic targets, have attracted widespread attention from many scholars and become a new research hotspot. Clinical research on selective PDE 4 and PDE 5 inhibitors has received special attention.
1. Mechanism of action
Phosphodiesterase has the function of hydrolyzing intracellular second messengers (cAMP or cGMP), thereby terminating the biochemical effects conducted by these second messengers. cAMP and cGMP play an important regulatory role in cell activities. The regulation of its concentration is mainly determined by the balance between the synthesis of adenylyl cyclase and the hydrolysis of phosphodiesterases (PDEs).
cAMP and cGMP act as inorganic pigments as second messengers and widely act on intracellular target organs, such as various PDEs. When external signals are transmitted across the membrane and cause a series of physiological reactions to activate nucleotide cyclase, cAMP and cGMP are produced, which are hydrolyzed and inactivated by the PDEs family into nucleoside 5-monophosphate (AMP). The balance between the synthesis of nucleotide cyclases and the hydrolytic inactivation of PDEs determines the concentrations of the second messengers cAMP and cGMP.
It is worth noting that cGMP is not only hydrolyzed by PDEs, but also can regulate the activity of some PDEs. For example, PDE2 can be stimulated by cGMP, while PDE3 can be inhibited by cGMP, and PDE4 is insensitive to cGMP.
2. Clinical effects
PDEs are widely distributed in the human body, and their physiological effects involve many research fields. As new therapeutic targets, PDEs have become a new research hotspot. The diversity and complexity of the phosphodiesterase superfamily provide new clues for the treatment of various diseases. Research on the structure of PDEs and PDEs inhibitors is conducive to exploring the selectivity of isoenzymes and is conducive to the development of new highly selective inhibitors.
PDEs isoenzymes are distributed in different tissues and have different physiological functions. Not only does each PDE family have specific substrates and regulatory characteristics, but each member of the Kao plasticizer family also has tissue-, cell-, and sub-cell-specific expression differences and participates in different signaling pathways. Selective PDEs inhibitors can specifically act on different isoenzymes and exert different effects. Therefore, PDEs have become attractive targets for drug development. The PDE isoenzyme family is involved in many fields such as cardiovascular, reproduction, anti-inflammatory, and immunity. With the development of research in molecular biology, biochemistry, and pharmacology, PDE isoenzymes have been subdivided into several subfamilies and sub-subfamilies. Drugs can act on a certain target with high specificity and greatly reduce toxic and side effects.
