Inhibition of \u03b2-site amyloid precursor protein cleaving enzyme 1 and cholinesterases by pterosins via a specific structure\u2212activity relationship with a strong BBB permeability

Susoma Jannat,Nam Sook Kang,Seong Su Hong,Ju Eun Kim,Dong Min Kim,Abinash Chandra Shrestha,Yun-Hyeok Choi,Chun Whan Choi,Jin-Mo Ku,Md Yousof Ali,Kee-Ho Lee,Ha Neul Ham,Woo Jung Kim,Anand Balupuri,Gil Hong Park,Jae Yoon Leem

doi:10.1038/s12276-019-0205-7

Abstract

We extracted 15 pterosin derivatives from Pteridium aquilinum that inhibited β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and cholinesterases involved in the pathogenesis of Alzheimer’s disease (AD). (2R)-Pterosin B inhibited BACE1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with an IC50 of 29.6, 16.2 and 48.1 µM, respectively. The Ki values and binding energies (kcal/mol) between pterosins and BACE1, AChE, and BChE corresponded to the respective IC50 values. (2R)-Pterosin B was a noncompetitive inhibitor against human BACE1 and BChE as well as a mixed-type inhibitor against AChE, binding to the active sites of the corresponding enzymes. Molecular docking simulation of mixed-type and noncompetitive inhibitors for BACE1, AChE, and BChE indicated novel binding site-directed inhibition of the enzymes by pterosins and the structure−activity relationship. (2R)-Pterosin B exhibited a strong BBB permeability with an effective permeability (Pe) of 60.3×10−6 cm/s on PAMPA-BBB. (2R)-Pterosin B and (2R,3 R)-pteroside C significantly decreased the secretion of Aβ peptides from neuroblastoma cells that overexpressed human β-amyloid precursor protein at 500 μM. Conclusively, our study suggested that several pterosins are potential scaffolds for multitarget-directed ligands (MTDLs) for AD therapeutics.

Highlights

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with characteristic clinical and pathological features, which are associated with the loss of Official journal of the Korean Society for Biochemistry and Molecular BiologyJannat et al Experimental & Molecular Medicine (2019) 51:12Reflecting the multifactorial and complex etiology of AD, the histopathological hallmarks, such as amyloid βprotein (Aβ) deposits[4]; dysfunctional signaling of acetylcholine (ACh) in certain areas of the brain[5]; τ protein neurofibrillary tangles[6]; metabolic pathways, such as those involving cAMP-responsive element binding protein (CREB)[7]; oxidative stress[8]; and inflammation[9], appear to play significant roles
Repeated column chromatography of the EtOAc-soluble fraction resulted in the isolation of nine derivatives, including (2R)-pterosin B (1), pterosin Z (2), (2S)-pterosin P (3), (3R)-pterosin D (4), (2S)-pterosin A (5), (2S,3R)-pterosin C (6), (2R,3R)-pterosin C (7), (2R)-pteroside B (8), and pteroside Z (9), with purities greater than 97% (Fig. 2)
The molecular structures of the enzyme/inhibitor complexes were further predicted to simulate binding between the pterosin derivatives and BACE1, AChE, and BChE

Summary

Introduction

Reflecting the multifactorial and complex etiology of AD, the histopathological hallmarks, such as amyloid βprotein (Aβ) deposits[4]; dysfunctional signaling of acetylcholine (ACh) in certain areas of the brain[5]; τ protein neurofibrillary tangles[6]; metabolic pathways, such as those involving cAMP-responsive element binding protein (CREB)[7]; oxidative stress[8]; and inflammation[9], appear to play significant roles. The amyloid hypothesis suggests that the accumulation and oligomerization of Aβ peptide in the brain plays a critical role in AD pathogenesis[10]. It has been clearly established that the overproduction of Aβ by the aspartic protease BACE1 and subsequent oligomerization result in toxic amyloid oligomers inducing neurodegeneration. BACE1 cleaves β-amyloid precursor protein (APP) and forms approximately 90% of the Aβ peptides[11,12]. Emerging evidence shows significant elevation of BACE1 in the presence of other

Methods

Results

Conclusion