Molecular Integrative Study on Inhibitory Effects of Pentapeptides on Polymerization and Cell Toxicity of Amyloid-β Peptide (1-42)

Overview

Journal Curr Issues Mol Biol

Publisher MDPI

Specialty Molecular Biology

Date 2024 Sep 27

PMID 39329958

Authors

Lianmeng Ye

Nuela Mankaa Che Ajuyo

Zhongyun Wu

Nan Yuan

Zhengpan Xiao

Wenyu Gu

Jiazheng Zhao

Yechun Pei

Yi Min

Dayong Wang

Affiliations

Soon will be listed here.

Abstract

Alzheimer's Disease (AD) is a multifaceted neurodegenerative disease predominantly defined by the extracellular accumulation of amyloid-β (Aβ) peptide. In light of this, in the past decade, several clinical approaches have been used aiming at developing peptides for therapeutic use in AD. The use of cationic arginine-rich peptides (CARPs) in targeting protein aggregations has been on the rise. Also, the process of peptide development employing computational approaches has attracted a lot of attention recently. Using a structure database containing pentapeptides made from 20 L-α amino acids, we employed molecular docking to sort pentapeptides that can bind to Aβ, then performed molecular dynamics (MD) analyses, including analysis of the binding stability, interaction energy, and binding free energy to screen ligands. Transmission electron microscopy (TEM), circular dichroism (CD), thioflavin T (ThT) fluorescence detection of Aβ polymerization, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and the flow cytometry of reactive oxygen species (ROS) were carried out to evaluate the influence of pentapeptides on the aggregation and cell toxicity of Aβ Two pentapeptides (TRRRR and ARRGR) were found to have strong effects on inhibiting the aggregation of Aβ and reducing the toxicity of Aβ secreted by SH-SY5Y cells, including cell death, reactive oxygen species (ROS) production, and apoptosis.

References

Vidal-Limon A, Aguilar-Toala J, Liceaga A . Integration of Molecular Docking Analysis and Molecular Dynamics Simulations for Studying Food Proteins and Bioactive Peptides. J Agric Food Chem. 2022; 70(4):934-943. DOI: 10.1021/acs.jafc.1c06110. View

Yuan N, Ye L, Sun Y, Wu H, Xiao Z, Fu W . Molecular Integrative Analysis of the Inhibitory Effects of Dipeptides on Amyloid β Peptide 1-42 Polymerization. Int J Mol Sci. 2023; 24(8). PMC: 10141046. DOI: 10.3390/ijms24087673. View

Kaur A, Goyal B . Identification of new pentapeptides as potential inhibitors of amyloid-β aggregation using virtual screening and molecular dynamics simulations. J Mol Graph Model. 2023; 124:108558. DOI: 10.1016/j.jmgm.2023.108558. View

Arakawa T, Kita Y, Ejima D, Tsumoto K, Fukada H . Aggregation suppression of proteins by arginine during thermal unfolding. Protein Pept Lett. 2006; 13(9):921-7. DOI: 10.2174/092986606778256171. View

Xu B, Jacobs M, Kostko O, Ahmed M . Guanidinium Group Remains Protonated in a Strongly Basic Arginine Solution. Chemphyschem. 2017; 18(12):1503-1506. DOI: 10.1002/cphc.201700197. View

Ghosh R, Sharma S, Chattopadhyay K . Effect of arginine on protein aggregation studied by fluorescence correlation spectroscopy and other biophysical methods. Biochemistry. 2009; 48(5):1135-43. DOI: 10.1021/bi802065j. View

Funke S, Willbold D . Peptides for therapy and diagnosis of Alzheimer's disease. Curr Pharm Des. 2012; 18(6):755-67. PMC: 3426787. DOI: 10.2174/138161212799277752. View

Schames J, Henchman R, Siegel J, Sotriffer C, Ni H, McCammon J . Discovery of a novel binding trench in HIV integrase. J Med Chem. 2004; 47(8):1879-81. DOI: 10.1021/jm0341913. View

Dror R, Dirks R, Grossman J, Xu H, Shaw D . Biomolecular simulation: a computational microscope for molecular biology. Annu Rev Biophys. 2012; 41:429-52. DOI: 10.1146/annurev-biophys-042910-155245. View

10.

Danho W, Swistok J, Khan W, Chu X, Cheung A, Fry D . Opportunities and challenges of developing peptide drugs in the pharmaceutical industry. Adv Exp Med Biol. 2009; 611:467-9. DOI: 10.1007/978-0-387-73657-0_201. View

11.

Tonali N, Dodero V, Kaffy J, Hericks L, Ongeri S, Sewald N . Real-Time BODIPY-Binding Assay To Screen Inhibitors of the Early Oligomerization Process of Aβ1-42 Peptide. Chembiochem. 2019; 21(8):1129-1135. PMC: 7217026. DOI: 10.1002/cbic.201900652. View

12.

Liu F, Dong X, He L, Middelberg A, Sun Y . Molecular insight into conformational transition of amyloid β-peptide 42 inhibited by (-)-epigallocatechin-3-gallate probed by molecular simulations. J Phys Chem B. 2011; 115(41):11879-87. DOI: 10.1021/jp202640b. View

13.

Allolio C, Magarkar A, Jurkiewicz P, Baxova K, Javanainen M, Mason P . Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore. Proc Natl Acad Sci U S A. 2018; 115(47):11923-11928. PMC: 6255155. DOI: 10.1073/pnas.1811520115. View

14.

Sinha S, Tam B, Wang S . Applications of Molecular Dynamics Simulation in Protein Study. Membranes (Basel). 2022; 12(9). PMC: 9505860. DOI: 10.3390/membranes12090844. View

15.

Luan B, Huynh T . Crystal-structures-guided design of fragment-based drugs for inhibiting the main protease of SARS-CoV-2. Proteins. 2021; 90(5):1081-1089. PMC: 8661981. DOI: 10.1002/prot.26260. View

16.

Mitchell D, Kim D, Steinman L, Fathman C, Rothbard J . Polyarginine enters cells more efficiently than other polycationic homopolymers. J Pept Res. 2000; 56(5):318-25. DOI: 10.1034/j.1399-3011.2000.00723.x. View

17.

Balbach J, Petkova A, Oyler N, Antzutkin O, Gordon D, Meredith S . Supramolecular structure in full-length Alzheimer's beta-amyloid fibrils: evidence for a parallel beta-sheet organization from solid-state nuclear magnetic resonance. Biophys J. 2002; 83(2):1205-16. PMC: 1302222. DOI: 10.1016/S0006-3495(02)75244-2. View

18.

Schmidt N, Mishra A, Lai G, Wong G . Arginine-rich cell-penetrating peptides. FEBS Lett. 2009; 584(9):1806-13. DOI: 10.1016/j.febslet.2009.11.046. View

19.

Liu H, Dong X, Liu F, Zheng J, Sun Y . Iminodiacetic acid-conjugated nanoparticles as a bifunctional modulator against Zn-mediated amyloid β-protein aggregation and cytotoxicity. J Colloid Interface Sci. 2017; 505:973-982. DOI: 10.1016/j.jcis.2017.06.093. View

20.

Sharma S, Sarkar S, Paul S, Roy S, Chattopadhyay K . A small molecule chemical chaperone optimizes its unfolded state contraction and denaturant like properties. Sci Rep. 2013; 3:3525. PMC: 3865464. DOI: 10.1038/srep03525. View