Phosphodiesteras (PDEs) are a class of enzymes that can hydrolyze the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). A variety of signaling and physiological activities. PDEs are encoded by 21 genes and are divided into 11 families (PDE1-11) based on their sensitivity to inhibitors and differences in amino acid sequences. The diversity of PDE family genes and their complex expression patterns suggest that different subtypes may have different pathological and physiological mechanisms. PDEs are involved in the occurrence and development of the pathological processes of inflammation, asthma, depression and other diseases, and can be used as important targets in the treatment of various complex diseases. Therefore, focusing on discovering lead compounds for PDEs inhibitors, including synthetic and natural sources, is the key to promoting the development of new drugs for this type of inhibitors.
At present, although synthetic PDEs inhibitor drugs have good effects in treating inflammation, asthma, neurodegenerative diseases, psoriasis and other diseases, they also have a series of adverse reactions. For example, the PDE4 inhibitor roflumilast is clinically used for the treatment of chronic obstructive pulmonary disease (COPD). The associated side effects are mainly nausea, headache, diarrhea and even insomnia and depression. Apremilast, a drug used to treat plaque psoriasis, can selectively inhibit PDE4A1A and thereby improve the signs and symptoms of patients with psoriatic arthritis. Its half inhibitory concentration (IC50) is 14 μmol/L . But it also has certain adverse reactions, such as nausea, vomiting, diarrhea, upper respiratory tract infections, tension headaches, and even depression. The PDE3 selective inhibitor milrinone is cardiotoxic. Therefore, these side effects greatly limit the clinical application scope and therapeutic prospects of PDEs inhibitors.
Natural products have always been the main source of drugs for disease prevention and treatment, and have a long history and solid foundation in the treatment of neurodegenerative diseases. Although synthetic drugs account for a large proportion in drug research and development, many drugs used clinically are directly or indirectly derived from natural products. Natural products remain one of the main sources of drugs or lead compounds to treat major diseases. Therefore, the search for highly efficient, low-toxic, and highly selective PDEs active inhibitory components from natural products has attracted more and more attention from scientists. This article introduces the active ingredients in natural products that have inhibitory effects on various PDEs subtypes, with a view to providing a reference for the development of new drugs targeting this target.
1 PDE1 and its natural inhibitors
The increase in intracellular Ca2+ concentration can cause disordered cell death and circulatory system disorders, which can lead to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, stroke and myocardial infarction. In the 1970s, scientists first demonstrated the existence of calcium ion-excited PDE1 through studies of mouse brain and bovine brain tissue. The PDE1 family represents the regulatory relationship between cyclic nucleotides and intracellular calcium ions, and has been shown to regulate the intracellular signal transduction pathways of Ca2+ and the cyclic nucleotides cAMP and cGMP. Research has found that PDE1 mainly exists in the brain, heart tissue, smooth muscle and cardiac muscle tissue, and plays an important role in motor behavior, learning and memory functional areas. Including three known calmodulin-dependent phosphodiesterase (CaM-PDEs) genes PDE1A, PDE1B, and PDE1C, which play a key role in regulating signal transduction in the tissues of the central nervous system.
Vincamine (1, Figure 1) isolated from Vinca minor L., a perennial vine of the Apocynaceae family, can regulate cerebral circulation to a certain extent and maintain neural dynamic balance. Qin Wencai and others found that vinblastine can improve the poor memory consolidation caused by anisodine and sodium nitrite to a certain extent. Vincamine can induce the production of prostaglandins and simultaneously change membrane flux and intramembrane Ca2+ distribution, thereby affecting Ca2+-mediated smooth muscle contraction and relaxation. Through structural modification, derivatives that are more efficient and less toxic than vincamine have been synthesized one after another. Among them, the most famous one is apovinblastine ethyl ester, also known as vinpocetine. Clinically, it can selectively increase cerebral blood flow and improve brain microcirculation and brain metabolism. In addition, the drug also has an auxiliary therapeutic effect on depression.
2 PDE2 and its natural inhibitors
PDE2 is mainly distributed in the brain, neurons, and heart, and is also distributed in the liver, placenta, and skeletal muscle. Its four subtypes (PDE2A1, PDE2A2, PDE2A3, and PDE2A4) have a high degree of homology [2]. PDE2 can not only hydrolyze cGMP and cAMP, but is also 30 times more selective for cGMP than cAMP. Its inhibitors can be used to treat heart disease, improve memory, and inhibit the formation of blood clots. Erthro-9-[2-hydroxyl-3-nonyl] ademine (EHNA) is a PDE2 inhibitor (IC50=0.8 μmol/L). It is often used as a reference substance for PDE2 inhibitory activity detection. However, due to its inhibition of adenosine deaminase The activity is very good, so it is subject to many restrictions in application.
Genistein (2, Figure 2), an isoflavone component widely present in plants of the Papilionoideae subfamily (Papilionoideae), has good inhibitory activity against PDE2, with an IC50 of (1.7±0.2 )μmol/L. At present, a variety of functional health products with genistein as the main component have been approved for clinical use in China.
3 PDE3 and its natural inhibitors, plays an important role in the treatment of hereditary color blindness, retinitis pigmentosa and other diseases. PDE8 is a cAMP-specific hydrolase that plays an important role in T cell activation, testosterone secretion, adrenal cortex hyperplasia, and thyroid function.
PDE9 only has 1 isoform, PDE9A, which can hydrolyze cGMP with high specificity. Its inhibitors are used to treat peripheral and central nervous system disorders, urological diseases, cancer, cardiovascular disease, and obesity. Four pairs of optical isomers (±)-torreyunliganA~H (34~41) were isolated from the taxa family Torreya yunnanensis Cheng et L. K. Fu. The activity test results against the PDE9A target showed that the IC50 of these compounds were all within 5.6～15.0 μmol/L, showing a moderate inhibitory effect compared with the positive control BAY73-6691 (IC50=49.7nmol/L).
PDE10 is a dual-specificity phosphodiesterase, and its inhibitors have good therapeutic effects on schizophrenia. Paeoniflorin (42) originates from the Paeoniaceae family and is an important component for analgesic, sedation, antipyretic and antispasmodic properties. This component can significantly upregulate the expression of PDE10A protein by regulating the expression of different substrate decomposing enzymes and affecting the content of two kinds of nucleotides. PDE11 may have a certain relationship with the occurrence of testes and epinephrine, but there is currently no specific inhibitor. The structures of natural inhibitors of other PDE families are shown in Figure 7.
8 Conclusion
This article reviews natural products that have inhibitory effects on various subtypes of PDEs. PDEs are a large family of enzymes, each of which is expressed to varying degrees in different cells. They are important targets for the treatment of some complex diseases. By isolating the active ingredients in natural products that act on various subtypes of PDEs, scientific researchers have discovered a series of natural ingredients with novel structures and excellent activity, providing lead compounds for the development of selective inhibitors of PDEs.
At present, natural inhibitors targeting PDE4 targets are the most reported, and there are relatively few studies on other families. However, because the mechanism of action of these compounds in regulating physiological activities of the body is still unclear, some compounds have only undergone simple in vitro activity screening and have not conducted in-depth studies on pharmacological effects and toxic reactions in vivo. In the future, it is necessary to combine in vivo and in vitro activity tests to conduct a comprehensive and objective activity evaluation. In terms of selecting medicinal materials for screening, the clinical experience of traditional Chinese medicine and natural medicine can be fully utilized to improve the hit rate of screening. For example, for screening of PDE4 inhibitors, some traditional Chinese medicines for clearing away heat and detoxification or relieving cough and asthma can be selected. At the same time, more efforts should be made to target the target The research on active ingredients cannot be limited to the research on the activity of crude extracts. Modern separation methods should be fully utilized in combination with activity tracking separation methods to more efficiently clarify the medicinal substances. In addition, although natural products have diverse structures, their activity, pharmacokinetics, physical and chemical properties, and safety do not meet the druggability requirements. Some compounds with good activity can be selected for structural modification and structure-activity relationship research to form natural PDEs. Provide strong support for inhibitor drug research and development.
