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In Silico design of AVP (4–5) peptide and synthesis, characterization and in vitro activity of chitosan nanoparticles

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Abstract

Background

Arginine-vasopressin (AVP) is a neuropeptide and provides learning and memory modulation. The AVP (4–5) dipeptide corresponds to the N-terminal fragment of the major vasopressin metabolite AVP (4–9), has a neuroprotective effect and used in the treatment of Alzheimer’s and Parkinson’s disease.

Methods

The main objective of the present study is to evaluate the molecular mechanism of AVP (4–5) dipeptide and to develop and synthesize chitosan nanoparticle formulation using modified version of ionic gelation method, to increase drug effectiveness. For peptide loaded chitosan nanoparticles, the synthesized experiment medium was simulated for the first time by molecular dynamics method and used to determine the stability of the peptide, and the binding mechanism to protein (HSP70) was also investigated by molecular docking calculations. A potential pharmacologically features of the peptide was also characterized by ADME (Absorption, Distribution, Metabolism and Excretion) analysis. The characterization, in vitro release study, encapsulation efficiency and loading capacity of the peptide loaded chitosan nanoparticles (CS NPs) were performed by Dynamic Light Scattering (DLS), UV–vis absorption (UV), Scanning Electron Microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy techniques. Additionally, in vitro cytotoxicity of the peptide on human neuroblastoma cells (SH-SY5Y) was examined with XTT assay and the statistical analysis was evaluated.

Results

The results showed that; hydrodynamic size, zeta potential and polydispersity index (PdI) of the peptide-loaded CS NPs were 167.6 nm, +13.2 mV, and 0.211, respectively. In vitro release study of the peptide-loaded CS NPs showed that 17.23% of the AVP (4–5)-NH2 peptide was released in the first day, while 61.13% of AVP (4–5)-NH2 peptide was released in the end of the 10th day. The encapsulation efficiency and loading capacity were 99% and 10%, respectively. According to the obtained results from XTT assay, toxicity on SHSY-5Y cells in the concentration from 0.01 μg/μL to 30 μg/μL were evaluated and no toxicity was observed. Also, neuroprotective effect was showed against H2O2 treatment.

Conclusion

The experimental medium of peptide-loaded chitosan nanoparticles was created for the first time with in silico system and the stability of the peptide in this medium was carried out by molecular dynamics studies. The binding sites of the peptide with the HSP70 protein were determined by molecular docking analysis. The size and morphology of the prepared NPs capable of crossing the blood-brain barrier (BBB) were monitored using DLS and SEM analyses, and the encapsulation efficiency and loading capacity were successfully performed with UV Analysis. In vitro release studies and in vitro cytotoxicity analysis on SHSY-5Y cell lines of the peptide were conducted for the first time.

Grapical abstract

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Abbreviations

AVP:

Arginine-vaspressin

CS NPs:

Chitosan nanoparticles

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

NGF:

Nerve growth factor

HSP:

Heat shock proteins

MD:

Molecular Dynamics

NVT:

Number of particles, Volume, and Temperature

NPT:

Number of particles, Pressure, and Temperature

Rg:

Gyration

RMSD:

Root mean square deviation

VMD:

Visual Molecular Dynamics

ADME:

Absorption, Distribution, Metabolism and Excretion

TED:

Total energy distribution

PdI:

Polydispersity index

FT-IR:

Fourier Transform Infrared

SEM:

Scanning Electron Microscopy

DLS:

Dynamic Light Scattering

EE:

Encapsulation Efficiency

LC:

Loading Capacity

PBS:

Phosphate Buffered Saline

XTT:

sodium 3,3′-[1(phenylamino)carbonyl]-3,4-tetrazolium]-3is(4-methoxy-6-nitro) benzene sulfonic acid hydrate

DMSO:

Dimethyl Sulfoxide

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Acknowledgements

Authors are also very thankful to Rita Podzuna for allowing using the docking program with Schrödinger’s Small-Molecule Drug Discovery Suite. In this study, the infrastructure of Applied Nanotechnology and Antibody Production Laboratory established with TUBITAK support (project numbers: 115S132 and 117S097) was used. Authors would thank to TUBITAK for their support.

Availability of data and materials

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Funding

This study was supported by the Research funds of Istanbul University [ONAP-2423].

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Authors and Affiliations

  1. Physics Department, Faculty of Science, Istanbul University, Vezneciler, 34134, Istanbul, Turkey

    Serda Kecel-Gunduz, Bilge Bicak & Aysen E. Ozel

  2. Department of Bioengineering, Faculty of Chemical and Metallurgical Engineering, Yildiz Technical University, 34220, Istanbul, Turkey

    Yasemin Budama-Kilinc & Rabia Cakir-Koc

  3. Graduate School of Natural and Applied Science, Yildiz Technical University, 34220, Istanbul, Turkey

    Tolga Zorlu

  4. Department of Physical Chemistry and EMaS, Universitat Rovira i Virgili, 43007, Tarragona, Spain

    Tolga Zorlu

  5. Institute of Graduate Studies in Sciences, Istanbul University, 34452, Istanbul, Turkey

    Bilge Bicak & Yagmur Kokcu

  6. Physics Department, Science and Letters Faculty, Istanbul Kultur University, Atakoy Campus, Bakirkoy, 34156, Istanbul, Turkey

    Sevim Akyuz

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  1. Serda Kecel-Gunduz
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  2. Yasemin Budama-Kilinc
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Contributions

SG: Participated in the design of the study, carried out the FTIR, band component analysis study, molecular docking, and molecular dynamic simulation and drafted the manuscript. YBK and TZ: Participated in the design of the experimental study, (synthesize and characterize nanoparticles) drafted the manuscript. RK: Participated in the design of the experimental study (cytotoxicity studies) drafted the manuscript. BB and YK: Participated in the design of the molecular docking and molecular dynamic simulation. AO and SA: Responsible for the study design and gave final approval of the version to be published. All authors read and approved the final manuscript and provide financial and administrative support.

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Correspondence to Serda Kecel-Gunduz.

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Kecel-Gunduz, S., Budama-Kilinc, Y., Cakir-Koc, R. et al. In Silico design of AVP (4–5) peptide and synthesis, characterization and in vitro activity of chitosan nanoparticles. DARU J Pharm Sci 28, 139–157 (2020). https://doi.org/10.1007/s40199-019-00325-9

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