A novel prolyl endopeptidase inhibitor, JTP-4819, with potential for treating Alzheimer's disease

Toide, Katsuo; Shinoda, Masahiko; Iwamoto, Yohko; Fujiwara, Takako; Okamiya, Kazuhiro; Uemura, Akinori

doi:10.1016/s0166-4328(97)86059-7

Cited by 38 publications

(29 citation statements)

References 41 publications

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“…Recently, it has been shown that caspase-6 and prolyloligopeptidase participate in the processing of amyloid precursor protein (13,16,17). In addition, inhibitors of prolyloligopeptidase have been reported to enhance cognition and are being explored for the treatment of Alzheimer's disease (18,19). The Bcl-2 associated protein Bax was also down-regulated after training, again indicating a possible antiapoptotic effect of enrichment training (20).…”

Section: Resultsmentioning

confidence: 99%

Effects of environmental enrichment on gene expression in the brain

Rampon

Jiang

Dong

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

555

359

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Section: Resultsmentioning

confidence: 99%

Effects of environmental enrichment on gene expression in the brain

Rampon

Jiang

Dong

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

555

359

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“…These ligands were either downloaded from PubChem or were constructed using CHEMDRAW software. Few other ligands like Y-29794 [46]–[48], UAMC [49], ono-1603 [50]–[51], S-17092 [52]–[56], SUAM-1221 [57]–[61], and JTP4819 [62]–[67] were also considered for this study. Coordinates were saved and subjected to CORINA for two dimensional to three dimensional conversions.…”

Section: Methodsmentioning

confidence: 99%

Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

Kaushik

Sowdhamini

2011

PLoS ONE

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Prolyl oligopeptidase (POP) is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD) simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases.

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“…Various authors have reported an unusually higher PEP levels in the patients suffering from AD and suggested that PEP might be one of the several factors involved in cognitive decline associated with aging (Lee & Paik, 2003;Tezuka et al, 1999). Therefore, PEP inhibition might have a therapeutic value in the treatment of AD and PEP inhibitors could be a novel anti-amnesic drug Schneider et al, 2002;Toide et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Radical scavenging, prolyl endopeptidase inhibitory, and antimicrobial potential of a cultured Himalayan lichenCetrelia olivetorum

Savale

Pol

Khare

et al. 2015

Pharmaceutical Biology

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Context: Lichens are source of natural bioactive compounds which are traditionally used to cure a variety of ailments. Objective: The objective of this study is to assess free radical scavenging, prolyl endopeptidase inhibitory (PEPI), and antimicrobial potential of a high altitude lichen species Cetrelia olivetorum (Nyl.) W. L. Culb. & C. F. Culb (Parmeliaceae). Materials and methods: Lichen C. olivetorum has been cultured in vitro, and optimized culture conditions were implemented in bioreactor to obtain high quantity of biomass for the study of radical scavenging, PEPI, and antimicrobial activities. Radical scavenging activity of methanol extract of Cetrelia olivetorum (MECO) was tested at 100 mg/mL, PEPI activity at 25 and 50 mg/mL, and antimicrobial activity at 5, 25, 50, and 100 mg/mL conc. All the biological activities of natural thallus extract and its derived culture extract were evaluated spectrophotometrically. Results: Murashige and Skoog medium supplemented with 3% glucose and 100 ppb indole-3-butyric acid (IBA) supported biomass growth at flask level and yielded 5.095 g biomass in bioreactor. MECO of both the cultured and the natural lichen exhibited half inhibiting concentration (IC 50 ) for radical scavenging activities in the range of 50-60 mg/mL, whereas the IC 50 value of standard antioxidants was found to be in the range of 12-29 mg/mL. The IC 50 value of lichen extract for PEPI activity was 144-288 mg/mL, whereas the IC 50 value of standard prolyl endopeptidase inhibitor, Z-pro-prolinal, was 57.73 mg/mL. As far as the antimicrobial activity of MECO is concerned, minimum inhibitory concentration (MIC) value of lichen extracts against tested microorganisms was obtained in the range of 50-104 mg/mL and found to be more effective than commercially available standard erythromycin. Discussion: Murashige and Skoog medium containing IBA was found to be suitable for maximum biomass production of C. olivetorum under bioreactor conditions. The cultured lichen biomass extract also showed antioxidant, PEPI, and antimicrobial potential. Conclusion: The present study indicates therapeutic potential of Himalayan lichen C. olivetorum against neurodegenerative diseases owing to its radical scavenging, PEPI, and antimicrobial activities. Further, the result encourages its commercial exploitation through mass culture for production of its bioactive components and their use in pharmaceutical and nutraceutical industries.

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A novel prolyl endopeptidase inhibitor, JTP-4819, with potential for treating Alzheimer's disease

Cited by 38 publications

References 41 publications

Effects of environmental enrichment on gene expression in the brain

Effects of environmental enrichment on gene expression in the brain

Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

Radical scavenging, prolyl endopeptidase inhibitory, and antimicrobial potential of a cultured Himalayan lichenCetrelia olivetorum

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