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Development of Peptide-Based Drugs for Alzheimer’s Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 14936

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Special Issue Editor

Dr. Anne Kasus-Jacobi

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Guest Editor

University of Oklahoma Health Sciences Center, Oklahoma City, United States
Interests: peptide drug discovery; multi-target peptide; antimicrobial peptide; Alzheimer’s disease; neurodegeneration; inflammation; corneal wound healing; corneal infection; multi-drug resistant infection

Special Issue Information

Dear colleagues,

Peptides represent a unique class of pharmaceutical compounds, between small molecules and proteins. This immense source of bioactive compounds offers great potential to solve previously hard-to-address oncological, metabolic, infectious, and neurodegenerative diseases.

The first peptide drug, insulin, marked the beginning of this new era in the pharmaceutical industry. Research in peptide-based therapeutics progressively increased since then, and started to really take center stage of novel drug development, only during the past decade. Remarkable advantages of peptides, such as their versatility, ability to disrupt interaction between macromolecules, and specificity for one or multiple targets, enables innovative approaches to the most challenging conditions. In addition, during the past decade, typical limitations to the pharmacological utilization of peptides (short half-life, low bioavailability, limited brain penetration, high production cost) have been and continue to be overcome by major breakthroughs in peptide chemistry.

This Special Issue intends to illustrate how peptide-based therapeutics are being developed for Alzheimer’s disease as an alternative approach to small molecule or antibody drugs, to address this unresolved public health priority.

We look forward to reading your original research article or up-to-date review contribution.

Dr. Anne Kasus-Jacobi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

peptide-based therapeutics
Alzheimer’s disease
amyloid beta
neuroinflammation
neurodegeneration

Published Papers (6 papers)

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Research

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13 pages, 2183 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Selecting Multitarget Peptides for Alzheimer’s Disease

by Anne Kasus-Jacobi, Jennifer L. Washburn, Riley B. Laurence and H. Anne Pereira

Biomolecules 2022, 12(10), 1386; https://doi.org/10.3390/biom12101386 - 27 Sep 2022

Cited by 2 | Viewed by 1861

Abstract

Alzheimer’s disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer’s disease, by targeting both neuroinflammation and neurodegeneration. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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14 pages, 1882 KiB

Open AccessEditor’s ChoiceArticle

Why the Ala-His-His Peptide Is an Appropriate Scaffold to Remove and Redox Silence Copper Ions from the Alzheimer’s-Related Aβ Peptide

by Paulina Gonzalez, Laurent Sabater, Emilie Mathieu, Peter Faller and Christelle Hureau

Biomolecules 2022, 12(10), 1327; https://doi.org/10.3390/biom12101327 - 20 Sep 2022

Cited by 3 | Viewed by 1763

Abstract

The progressive, neurodegenerative Alzheimer’s disease (AD) is the most widespread dementia. Due to the ageing of the population and the current lack of molecules able to prevent or stop the disease, AD will be even more impactful for society in the future. AD is a multifactorial disease, and, among other factors, metal ions have been regarded as potential therapeutic targets. This is the case for the redox-competent Cu ions involved in the production of reactive oxygen species (ROS) when bound to the Alzheimer-related Aβ peptide, a process that contributes to the overall oxidative stress and inflammation observed in AD. Here, we made use of peptide ligands to stop the Cu(Aβ)-induced ROS production and we showed why the AHH sequence is fully appropriate, while the two parents, AH and AAH, are not. The AHH peptide keeps its beneficial ability against Cu(Aβ)-induced ROS, even in the presence of Zn^II-competing ions and other biologically relevant ions. The detailed kinetic mechanism by which AHH could exert its action against Cu(Aβ)-induced ROS is also proposed. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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Review

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28 pages, 1364 KiB

Open AccessReview

Alzheimer’s Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound

by Narjes Baazaoui and Khalid Iqbal

Biomolecules 2022, 12(10), 1409; https://doi.org/10.3390/biom12101409 - 02 Oct 2022

Cited by 8 | Viewed by 2310

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with an insidious onset and multifactorial nature. A deficit in neurogenesis and synaptic plasticity are considered the early pathological features associated with neurofibrillary tau and amyloid β pathologies and neuroinflammation. The imbalance of neurotrophic factors with an increase in FGF-2 level and a decrease in brain derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) in the hippocampus, frontal cortex and parietal cortex and disruption of the brain micro-environment are other characteristics of AD. Neurotrophic factors are crucial in neuronal differentiation, maturation, and survival. Several attempts to use neurotrophic factors to treat AD were made, but these trials were halted due to their blood-brain barrier (BBB) impermeability, short-half-life, and severe side effects. In the present review we mainly focus on the major etiopathology features of AD and the use of a small neurotrophic and neurogenic peptide mimetic compound; P021 that was discovered in our laboratory and was found to overcome the difficulties faced in the administration of the whole neurotrophic factor proteins. We describe pre-clinical studies on P021 and its potential as a therapeutic drug for AD and related neurodegenerative disorders. Our study is limited because it focuses only on P021 and the relevant literature; a more thorough investigation is required to review studies on various therapeutic approaches and potential drugs that are emerging in the AD field. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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25 pages, 1978 KiB

Open AccessEditor’s ChoiceReview

From Small Peptides to Large Proteins against Alzheimer’sDisease

by Pasquale Picone, Tiziana Sanfilippo, Sonya Vasto, Sara Baldassano, Rossella Guggino, Domenico Nuzzo, Donatella Bulone, Pier Luigi San Biagio, Emanuela Muscolino, Roberto Monastero, Clelia Dispenza and Daniela Giacomazza

Biomolecules 2022, 12(10), 1344; https://doi.org/10.3390/biom12101344 - 22 Sep 2022

Cited by 5 | Viewed by 2056

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau (p-Tau) located in the cytoplasm of neurons. Although the research has made relevant progress in the management of the disease, the treatment is still lacking. Only symptomatic medications exist for the disease, and, in the meantime, laboratories worldwide are investigating disease-modifying treatments for AD. In the present review, results centered on the use of peptides of different sizes involved in AD are presented. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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15 pages, 1892 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Comparison of Tau and Amyloid-β Targeted Immunotherapy Nanoparticles for Alzheimer’s Disease

by Yara Mashal, Hosam Abdelhady and Arun K. Iyer

Biomolecules 2022, 12(7), 1001; https://doi.org/10.3390/biom12071001 - 18 Jul 2022

Cited by 6 | Viewed by 2990

Abstract

Alzheimer’s disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-β plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, and brain damage is irreversible. Several therapeutic targets have been defined mainly related to two hypotheses of AD: the tau hypothesis and the amyloid-β hypothesis. Here, we intend to investigate and to compare different therapeutic approaches for AD, mainly based on nanoparticles (NPs) targeted at the brain and at the pathological hallmarks of the disease. We analyzed preclinical trials that have successfully improved drug bioavailability in the brain by using targeted nanocarriers towards either tau, amyloid-β, or both. We then compared these trials to find out which protein is more efficient in therapeutic targeting. We found that the search for a cure was mostly based on the amyloid-β hypothesis, with Aβ dysplasia emerging as the most confirmed and convincing therapeutic target. Targeted NPs have proven useful to enhance both the bioavailability and the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted NPs for combined therapies. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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19 pages, 688 KiB

Open AccessReview

Amylin and Secretases in the Pathology and Treatment of Alzheimer’s Disease

by Som Singh, Felix Yang, Andy Sivils, Victoria Cegielski and Xiang-Ping Chu

Biomolecules 2022, 12(7), 996; https://doi.org/10.3390/biom12070996 - 17 Jul 2022

Cited by 5 | Viewed by 3113

Abstract

Alzheimer’s disease remains a prevailing neurodegenerative condition which has an array physical, emotional, and financial consequences to patients and society. In the past decade, there has been a greater degree of investigation on therapeutic small peptides. This group of biomolecules have a profile of fundamentally sound characteristics which make them an intriguing area for drug development. Among these biomolecules, there are four modulatory mechanisms of interest in this review: alpha-, beta-, gamma-secretases, and amylin. These protease-based biomolecules all have a contributory role in the amyloid cascade hypothesis. Moreover, the involvement of various biochemical pathways intertwines these peptides to have shared regulators (i.e., retinoids). Further clinical and translational investigation must occur to gain a greater understanding of its potential application in patient care. The aim of this narrative review is to evaluate the contemporary literature on these protease biomolecule modulators and determine its utility in the treatment of Alzheimer’s disease. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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