The Natural Product Berberine is a Human Prolyl Oligopeptidase Inhibitor

Abstract

Prolyl oligopeptidase is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy terminus. This peptidase has been associated with schizophrenia, bipolar affective disorder, and related neuropsychiatric disorders, and therefore may have important clinical implications. Among the strategies used to find novel prolyl oligopeptidase inhibitors, traditional Chinese medicinal plants provide a rich source of unexplored compounds. We used (19)F NMR spectroscopy to search for new prolyl oligopeptidase inhibitors in a library of traditional Chinese medicine plant extracts. Several extracts were identified as powerful inhibitors of this peptidase. The alkaloid berberine was the prolyl oligopeptidase inhibitory molecule isolated from Rhizoma coptidis extract. Berberine inhibited prolyl oligopeptidase in a dose-dependent manner. As berberine is a natural compound that has been safely administered to humans, it opens up new perspectives for the treatment of neuropsychiatric diseases. The results described herein suggest that the initiation of clinical trials in patients with schizophrenia, bipolar affective disorder, or related diseases in which cognitive capabilities are affected should be undertaken with either the extract or pure BBR.

Benzimidazolium Salts as Small, Nonpeptidic and BBB‐Permeable Human Prolyl Oligopeptidase Inhibitors

“…[26] Regarding the potency of our best inhibitors when compared with typical reference compounds such as ZPP, [18] it should be considered that the latter is a covalent inhibitor that reacts with the serine in the enzyme active site. These kinds of highly reactive, covalent inhibitors may be inadequate for clinical use because of stability problems and serious side effects, in addition to limitations in accessing the central nervous system (CNS), as brain entry is hindered by the blood-brain barrier (BBB).…”

“…The alkaloid berberine was isolated as the POP inhibitory molecule in Rhizoma coptidis extract. [26] In the present work we report our results on a new class of POP inhibitors that share a benzimidazolium moiety that recalls the isoquinolinium structure present in berberine. We have prepared a small compound library of potential POP inhibitors applying recent results on the development of new multicomponent reactions (MCRs) [27] which allowed straightforward access to a variety of diversely substituted heteroaromatic structures (benzonaphthyridines, pyranoquinolines, and benzimidazolium salts).…”

Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders

“…Surprisingly, antipsychotic drugs do not have any action on this enzyme (Maes et al, 1995). Berberine inhibits prolyl oligopeptidase (IC50 value of 145 ± 19 μM) in a concentration-dependent manner (Tarrago et al, 2007). It is hypothesized that berberine, because of its prolyl-oligopeptidase-inhibiting property, might be useful in the treatment of schizophrenia.…”

“…Prolyl oligopeptidase family enzymes are cytosolic serine peptidases that are known to hydrolyze prolinecontaining peptides at the carboxy terminus (Tarrago et al, 2007). These enzymes regulate the activity of biologically active peptides and peptide hormones that are implicated in various diseases, including schizophrenia, memory loss, depression, diabetes, and trypanosomiasis (Rea and Fülöp, 2006).…”

Molecular and Celluar Mechanism Studies on Anticancer Effects of Chinese Medicines

“…cholera and bacterial diarrhea) by their antibacterial and antiviral effects, treatment of hypercholesterolemic patients and type 2 diabetes by hypolipidemic effects, and various experimental heart diseases, such as heart failure,cardiac dysfunction, pressure-overload induced cardiac hypertrophy . Berberine may help in neuropsychiatric diseases by inhibiting Prolylligopeptidase, a peptidase associated to schizophrenia, bipolar affective disorder and related conditions (Tarrago et al, 2007). Recently, the most attractive pharmacological effect of CR and berberine is its anticancer activities ).…”