Antimicrobial Peptides, An Avenue to Treat Neurodegradation?

Shimon Shatzmiller^*, Inbal Lapidot & Galina Zats-Mordechai

Department of Chemical Sciences, Ariel University, Israel

*Correspondence to: Dr. Shimon Shatzmiller, Department of Chemical Sciences, Ariel University, Israel.

Copyright © 2018 Dr. Shimon Shatzmiller, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction
Alzheimer’s disease (AD) is the most generic form of dementia in the elderly and its prevalence is set to increase rapidly in coming decades. However, there are yet no available drugs that can halt or even stabilize disease progression. One of the main pathological features of AD is the presence in the brain of senile plaques mainly composed of aggregated β amyloid (Aβ), a derivative of the longer amyloid precursor protein (APP).

The amyloid hypothesis proposes that the accumulation of Aβ within neural tissue is the initial event that triggers the disease. The Amyloid hypothesis [3] suggests Amyloid-β (Aβ) as main peptides produced in the brain by digestion of the amyloid precursor peptide (APP) by β, and secretase enzymes [4,5]. β amyloid aggregation inhibitors can be small molecules as candidate drugs for therapy of Alzheimer’s disease [6a,b]. Also Amylin is a 37-amino-acid polypeptide [7] which is co-secreted with insulin [8]. After its identification in 1986 [9], there has been a rapid expansion of knowledge relating to amylin, which has already been translated into clinical practice. Amylin has been established as a glucoregulatory, neuroendocrine hormone in animals [10]; however, its role in human physiology is less well defined. Pramlintide, an amylin analogue, has been developed, and is now used in the treatment of diabetes. It is a pancreatic enzyme characteristic to Diabetes Mellitus type II (DM), the “Islet peptide”, is playing a key role in the development of neurodegenerative disorders [5b,11]. The Aβ are antimicrobial enzymes. Aβ and Amylin are both antimicrobial peptides. Also, the Amylin Protein of Diabetes Mellitus is an Antimicrobial Peptide [12].

Conformational disease is a general term often used to identify a number of disorders that are characterized by aggregation and deposition of specific proteins. Although the physiological roles of some of these aggregation-prone proteins have yet to be fully elucidated [13], it is possible to distinguish several different pathologies depending on the aggregation of a specific protein, i.e. b-amyloid for Alzheimer’s disease [14], a-synuclein for Parkinson’s disease, etc. In these diseases, the proteins in question are known to convert from their native functional state into highly organized fibrillar aggregates. In the case of amylin [15,16], the observation of amyloid deposits in islets Langerhans of individuals with type 2 diabetes was for a long time considered not important, probably because while researchers studying other pathologies were looking for a protein to blame that could be responsible for the possible pathogenic mechanism, the research field of type 2 diabetes was already well established and mainly directed towardsthe study of insulin resistance [17]. possible pathogenic mechanism, the research field of type 2 diabetes was already well established and mainly directed towards the study of insulin resistance [18].

Currently, only palliative therapies [19] for the AD are available. Acetylcholine inhibitors [20] like Donepezil, Galantamine, and the NMDA receptor [21] antagonist Memantine have been approved for clinical use as a treatment for cognitive symptoms. The five drugs are currently available: four cholinesterase inhibitors and a N-methyl-D-aspartate receptor antagonist.

However, these are only effective for a limited amount of time, between 6 to 12 months, and for half of the patients affected with milder forms of Alzheimer’s. The current FDA approved drugs for the AD do not cure the disease, they are targeted to aid in the misery of the terminal disease by soothing their pains and helplessness, as agents that provide better function of the synaptic processes. Some believe that the inhibitors preventing A aggregation are a new doorway toward new drugs to cure Alzheimer’s disease [22].

Small molecule probes of protein aggregation [23] are a strategy accepted in neurodegenerative disease research for more than two decades. During that time the complex and obscure situation has become clearer. However, many protein misfolding are contributing to neurosecretion [10,24] and are finally appearing as different, but related diseases.

Sketches or structures, where available, of amyloid precursors and peptides associated with various human pathologies. PDB IDs: b2-microglobulin D76N, 4fxl, transthyretin, 3cn4, immunoglobulin light chain, 1bre , insulin, 1zeh , lysozyme, 5fhw, human prion: 1i4m . These unrelated amyloid sequences assemble into highly organized cross-b amyloid fibrils (center) via an array of oligomers that, thus far, have largely eluded structural characterization. A number of possible oligomeric structures have been proposed, including dimers, domain swapped dimers , hexamers and dodecamers , cylindering , nanotubes and pore forming oligomers. The structure of (insulin) fibrils shown in the center is taken from, with permission. Credit ref. 10

-Helix and Β-Sheet Breakers and Peptidomimetics
Synthetic peptide derivatives, termed ‘β-sheet breakers’ [10], have been developed that are able to inhibit amyloid formation by binding to monomeric precursors, or by preventing fibril elongation by blocking fibril ends. Substitution of key residues in synthetic peptides corresponding to the amyloid core regions with prolines, or incorporating N-methyl modified amino acids [25], prevents hydrogen bond formation crucial to the cross-β structure. Clever use of these strategies within cyclic peptides has been used to create amyloid inhibitors and has enabled oligomeric intermediates to be isolated and characterized [26].

Foldamers are a very prominent class of α-helix mimetic peptides. They are composed of β-amino acid α/β- amino acid oligomers), or N-substituted glycine residues (peptoids). Such foldamers have been shown to inhibit the proteolytic activity of γ-secretase, an enzyme that is involved in the processing of amyloid-β (Aβ) in Alzheimer’s disease, by blocking the initial substrate binding site of γ-secretase [27, 32].

The “Amyloid peptides” tend to aggregate in the brain to form the plaques and tangles that destroy the neurons in the brain [28] byways that end in apoptosis of the nerve cells, probably by the destruction of the synapses [29].

As illustrated above, more and more evidence accumulates showing that there is a connection between neurosecretion and diabetes. Reports in the literature point to the role of diabetes peptides, both Insulin, Amylin are active in the brain. They have a role in the development of neurological symptoms [30]. A fragment of Amylin (islet peptide) is a trigger of neurodegeneration leading to Alzheimer’s and Parkinson’s diseases. However, on this basis, only a few attempts to suggest peptide-based research for curing and diagnosing the fatal diseases are published [31].

The Antimicrobial peptides: AA-peptides are enzymatically stable, display excellent antimicrobial activity and show promise in many other biological applications such as cancer,

Alzheimer’s disease and biomaterial science [32] AApeptides activity and show promise in many other biological applications such as cancer, Alzheimer´s disease and biomaterial science. [33], the class of peptides in which Aβ and Amylin could be classified, are a currently investigated class of potential drug candidates. Both forms of DM contribute to accelerated cerebral atrophy [34] and to the presence of heightened white matter abnormalities. Rational design of peptide mimics that prevent aggregation of Aβ is shown below [13]:

The combination of established experimental methods with multi-scale state-of-the-art computational methods have shown that castalgine, vescalagin, SEN304 and inh3 are promising molecules to prevent the amyloid- beta peptide aggregation, and to reduce the cellular toxicity of the peptide [35].

The pioneering work of Ehud Gazit [36], Susanne Aileen Funke and Dieter Willbold [6], the are seeking for peptides that can cross the BBB and interfere with the aggregation of Aβ in the living brain has opened a new avenue for AMP and their surrogates as potential agents for neurodegenerative diseases.

The significance of biological activity is determining factor in search of new drug and diagnostics for neurodegeneration. However, The biological testing can be carried out on many living organisms from worms and fly to mice and more complex organisms. Such tests are cumbersome and expensive. The fact that antimicrobial agents like peptide [37]and their surrogates are potential candidates can have carried us in a simple Minimum Inhibitory Concentrations (MIC) experiments experiments and the indication for toxicity in a hemolysis determination of human red blood cells. The preliminary antimicrobial test approach may accelerate the pace in which candidates then tested for an AD for example.

Peptides and Peptide Surrogates in Amyloid Diseases Research
Despite great diversity in the primary amino acid sequence of proteins, the oligomers of different misfolded [38] amyloidogenic proteins (hyper phosphorylated tau [39], amyloid-synuclein) elicit toxicity by common mechanisms. This toxicity involves membrane perturbations, calcium dysregulation, the accumulation of reactive oxygen species, endoplasmic reticulum (ER)-stress, impairment of the ubiquitin-proteasome system, and the activation of apoptotic signaling pathways. Indeed, it is hypothesized that the initiation of NDDs is a result of ER-stress, damaged mitochondria, and loss of Ca^2+- and protein homeostasis.

It is reported that γ-peptide-based small-molecule ligands that inhibit Aβ aggregation. (GRKKRRQRRRPQ) was able to bind to HIV TAR RNA and BIV TAR RNA with

Comparable selectivity and specificity to that of the Tat peptide. Furthermore, -AApeptide mimics of RGD peptides (including 64Cu-labelled compounds), and of fMLF (a selective formyl peptide receptor agonist) have been reported. Also, -AApeptides have been shown to disrupt A aggregation in Alzheimer’s disease, and to have potential applications in biomaterial science.

The classes of antimicrobial peptidomimetics are of interest owing to the convenient synthesis of the corresponding building blocks and their assembly by using standard solid-phase procedures [40].

Dihydropyridine (DHP) Based Agents [41]
We prepared 1,4-Dihydropyridine (DHP) based peptide mimics and had shown that they are antibacterial agents [42].

Similar DHP derivatives were shown to have a neuroprotective effect in a transgenic mouse model of Alzheimer’s disease [43].

It was also reported that Selective Antihypertensive Dihydropyridines Lower Aβ Accumulation by Targeting both the Production and the Clearance of Aβ across the Blood-Brain Barrier. Several large populationbased or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer disease (AD) [44].

Calcium channel blockers and dementia as reported in the last years by researchers. It became established that In Alzheimer’s disease, enhanced calcium load might be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration.It is based on the “Calcium hypothesis of dementia.”

Among the antihypertensive DHPs tested [45], a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro [28], whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of an AD and improved Aβ clearance across the blood-brain barrier (BBB), whereas amlodipine and nifedipine were ineffective showings that the Aβ-lowering activity of the DHPs is independent of their antihypertensive activity.

Disruptions of normal calcium (Ca 2+ ) homeostasis in human aging processes, are well documented [27]. The existence of at least four distinct types of Ca 2+ channels, L-, T-, P-, and N-, have been reported in the central nervous system. Binding sites for clinically useful dihydropyridines (DHP) and phenylalkylamines (PA) [46]are located on the L-type Ca 2+ channels. In the present study, DHPbinding parameters were determined in various brain areas obtained at autopsy from Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD) disease patients, and healthy age-matched controls as a means to assess the integrity of L-type channels in these neurological disorders often associated with the aging brain.

DHP and PA receptor binding parameters were not significantly altered in any of the brain regions studied in AD and PD.

However, a significant decrease in the maximal binding capacity of [3H]PN200-110 was observed in the striatum of HD patients.

Taken together, this suggests that DHP and PA binding sites associated to L-type Ca2+ channels are mostly preserved in AD and PD brains. Accordingly, the use of DHP- and PA-related drugs in these neurological disorders should not be hindered by deficits in their related Ca2÷ channel binding proteins.

Intracellular Ca²⁺ signaling is fundamental to neuronal physiology and viability. Due to its ubiquitous roles, disruptions in Ca²⁺ homeostasis are implicated in diverse disease processes and have become a major focus of study in multifactorial neurodegenerative diseases such as Alzheimer’s disease.

Azepine and Diazepine Based Peptide Mimics for AD
In the last years, there is an increasing evidence of the implication of free radicals and reactive oxygen species in a variety of diseases and pathophysiological events including inflammation, cancer, myocardial infarction, arthritis and neurodegenerative disorders [47]. Azepine [48] based drug candidates a key role in this effort. Reactive Oxygen Species (ROS) have been suggested to play a key role in the pathophysiology of myocardial reperfusion injury. Peptide isosteres have been useful for demonstrating that presenilin [49] is the catalytic subunit of -secretase and probing the active site. Presenilin-1 and -2 Are Molecular Targets for g-Secretase Inhibitors [50].

Gamma-secretase inhibitors for Alzheimer’s disease [51]: balancing efficacy and toxicity. Based on this hypothesis, compounds that inhibit gamma-secretase, one of the enzymes responsible for forming Aβ, are potential therapeutics for AD. Preclinical studies clearly establish that gamma-secretase inhibitors can reduce brain Aβ in rodent models [52]. The discovery of Begacetate [53], was giving new hope to AD patients.

There is a potential role of antimicrobial peptides in the early onset of Alzheimer’s disease. In fact, one of the promising natural product, the semagacestat is a modified peptide compound. It is one of the most advanced candidates in respect to the therapy of Alzheimer’s. Semagacestat is a gamma-secretase inhibitor for the potential treatment of Alzheimer’s disease [54]. γ-Secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment [55].

Although there was published a few US patent on Azepine derivatives as gamma-secretase inhibitors, we have prepared [56] an analog based on a pentapeptide chain (KAAAL) and a - turn mimic the benzodiazepine unit. The patent does not mention Diazepine derivatives as gamma-secretase inhibitors. We checked the antibacterial activity to both the DHP based and the Benzodiazepine based peptidomimetic which both were active antibacterial agents.

Astra-Zeneca explored the g-secretase inhibition and noch inhibition with some diazepine based peptide mimics follows:

Small Molecules are Targeted as Neurodegeneration Diseases Future Drugs [4]
There are new prospects and strategies for drug target discovery in Neurodegenerative disorders. The future of the neurological therapeutic development depends upon effective disease modification strategies centered on carefully investigated targets. Pharmaceutical research endeavors that probe for a much deeper understanding of disease pathogenesis, and explain how adaptive or compensatory mechanisms might be engaged to delay disease onset or progression, will produce the needed breakthroughs. Below, we discuss the prospects for new targets emerging out of the study of brain disease genes and their associated pathogenic pathways. We describe a general experimental paradigm that we are employing across several mouse models of neurodegenerative disease to elucidate molecular determinants of selective neuronal vulnerability. We outline key elements of our target discovery program and provide examples of how we integrate genomic technologies, neuroanatomical methods, and mouse genetics in the search for neurodegenerative disease targets.

The general approach tend to encumber many neurological brain diseases and seek the diagnosis and cure of the very essential dysfunction sites with decoy therapeutics.

Focus is on the general situation that combines many diseases and efforts are placed in the understanding of the biological processes leading to the grim situation an effort to eliminate the factors that take the undesired biologically imposed process and modify it in such a manner that successive events which lead to the appearance of the diseases will be eliminated or slowed down.

With AD, Diabetes, CJD, and more, Aβ aggregation is the first target. The stacking of the Aβ molecules to fibrils and further is a crucial stage in the development of the diseases.

Conclusions
The efforts towards the effective curing efforts of neurodegenerative diseases (also called sometimes conformational diseases), and in the front-line Alzheimer’s and Parkinson’s diseases is gaining a new perspective. The joining of Diabetes and neuro-degradation as leading concept for the better understanding and more accurate and profound understanding is moving the focus of attention to new ideas based on peptides and their surrogate to block pathogenic processes in the development of biological agents that destroy the brain cells, Aside insulin, Amylin [59] has become an additional digestive peptide that is considered as target for exploration and exploiting the biological processes for the design of novel, peptide mimics, anti neuro-degenerative agents.

The new hope in the efforts toward new treatment, quantitative early diagnostics, mechanisms of action and anti-infective treatments or a new serum for vaccination, are the aspiration of many which will finally improve and might solve the long-standing problems in neuro-degradation.

Bibliography

1. a) Rudolph Tanzi, E. & Lars Bertram (2005). Twenty Years of the Alzheimer’s Review Disease Amyloid Hypothesis: A Genetic Perspective. Cell, 120(4), 545-555.
   b) Hardy, J. & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 297(5580), 353-356.
   c) Eric Karran, Marc Mercken & Bart De Strooper (2011). The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nature Reviews Drug Discovery, 10(9), 698-712.
2. a) Leszek, J., Trypka, E., Tarasov, V. V., Ashraf, G. M. & Aliev, G. (2017). Type 3 Diabetes Mellitus: A Novel Implication of Alzheimers Disease. Curr Top Med Chem., 17(12), 1331-1335.
   b) Diabetes UK, Type 3 Diabetes.
   c) Eric Steen, Benjamin Terry, M., Enrique Rivera, J., Jennifer, L. C., et al. (2005). Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease - is this type 3 diabetes? Journal of Alzheimer’s Disease, 7(1), 63-80.
3. Dennis Selkoe, J. (2006). Toward a Comprehensive Theory for Alzheimer’s Disease Hypothesis: Alzheimer’s Disease Is Caused by the Cerebral Accumulation and Cytotoxicity of Amyloid -Protein. Annals of the New York Academy of Sciences, 924(1), 1-193.
4. Tomohiro Chiba (2013). Emerging Therapeutic Strategies in Alzheimer's Disease. Neurodegenerative Diseases, book edited by Uday Kishore.
5. Ruth MacLeod, Ellin-Kristina Hillert, Ryan Cameron, T. & George Baillie, S. (2015). The role and therapeutic targeting of α-, β- and γ-secretase in Alzheimer's disease. Future Science OA, 1(3).
6. a) Jyothi Ghanta, Chih-Lung Shen, Laura Kiessling, L. & Regina Murphy, M. (1996). A Strategy for DesigningInhibitors of β - Amyloid Toxicity. The Journal Of Biological Chemistry, 271(47), 29525-29528.
   b) Wen Fu, Aarti Patel, Ryoichi Kimura, Rania Soudy & Jack Jhamandas, H. Amylin Receptor:A Potential Therapeutic Targetfor Alzheimer’s Disease. Trends in Molecular Medicine, 23(8), 709-720.
7. Cooper, G. J., Willis, A. C., Clarke, A., et al. (1987). Purification and characterization of a peptide from amyloid rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA, 84(23), 8628-8632.
8. Cooper, G. J. S. (1995). Amylin compared with calcitonin gene-related peptide: structure, biology and relevance to metabolic disease. Endocr Rev., 15(2), 163-201.
9. Cooper, G. J. S. (1995). Amylin compared with calcitonin gene-related peptide: structure, biology and relevance to metabolic disease. Endocr Rev., 15(2), 163-201.
10. Castillo, M. J., Scheen, A. J. & LeFebvre, P. J. (1995). Amylin/islet amyloid polypeptide: biochemistry, physiology, pathophysiology. Diab Metab., 21(1), 3-25.
11. a) Lydia Young, M., Ping Cao, Daniel Raleigh, P., Alison Ashcroft, E. & Sheena Radford, E. (2014). Ion Mobility Spectrometry-Mass Spectrometry Defines the Oligomeric Intermediates in Amylin Amyloid Formation and the Mode of Action of Inhibitors. J. Am. Chem. Soc., 136(2), 660-670.
    b) Per Westermark, Arne Andersson & Gunilla Westermark, T. (2011). Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus. Physiological Reviews, 91(3), 795-826.
12. Guangshun Wang (2014). Human Antimicrobial Peptides and Proteins. Pharmaceuticals, 7(5), 545-594.
13. Giuffrida, M. L., Caraci, F., Pignataro, B., Cataldo, S., De Bona, P., et al. (2009). Beta-amyloid monomers are neuroprotective. J. Neurosci., 29(34), 10582-10587.
14. De Toma, A. S., Salamekh, S., Ramamoorthy, A. & Lim, M. H. (2012). Misfolded proteins in Alzheimer’s disease and type II diabetes. Chem. Soc. Rev., 41(2), 608-621.
15. Phillips, L. K. & Horowitz, M. (2006). Amylin. Curr. Opin. Endocrinol. Diabetes, 13(2), 191-198.
16. Cao, P., Abedini, A. & Raleigh, D. P. (2013). Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology. Curr. Opin. Struct. Biol., 23(1), 82-89.
17. Per Westermark, Arne Andersson & Gunilla Westermark, T. (2011). Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus. Physiological Reviews, 91(3), 795-826.
18. Per Westermark, Arne Andersson & Gunilla Westermark, T. (2011). Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus. Physiological Reviews, 91(3), 795-826.
19. Susanne Aileen Funke & Dieter Willbold (2012). Peptides for Therapy and Diagnosis of Alzheimer’s Disease. Current Pharmaceutical Design, 18(6), 755-767.
20. Klugman, A., Naughton, D. P., Isaac, M., Shah, I., Petroczi, A. & Tabet, N. (2012). Antioxidant enzymatic activities in alzheimer’s disease: the relationship to acetylcholinesterase inhibitors. Journal of Alzheimer’s Disease, 30(3), 467-474.
21. Sandra Amor, Fabiola Puentes, David Baker & Paul van der Valk (2010). Inflammation in neurodegenerative diseases. Immunology, 129(2), 154-169.
22. Cohen Fred, E. & Kelly Jeffery, W. (2003). Therapeutic approaches to protein-misfolding diseases. Nature, 426(6968), 905-909.
23. Lydia Young, M., Alison Ashcroft, E. & Sheena Radford, E. (2017). Small molecule probes of protein aggregation. Current Opinion in Chemical Biology, 39, 90-99.
24. Takahashi, T. & Hisakazu Mihara (2008). Peptide and Protein Mimetics Inhibiting Amyloid-Peptide Aggregation. Accounts Of Chemical Research, 41(10), 1309-1318.
25. Gordon, D. J., Tappe, R. & Meredith, S. C. (2002). Design and characterization of a membrane permeable N-methyl amino acid-containing peptide that inhibits Aβ1-40 fibrillogenesis. J. Peptide Res., 60(1), 37-55.
26. Rajasekhar, K., Suresh, S. N., Ravi Manjithaya & Govindaraju, T. (2015). Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer’s Disease. Scientific Reports, 5(8139).
27. a) Groß, A., Hashimoto, C., Sticht, H. & Eichler, J. (2016). Synthetic Peptides as Protein Mimics. Front. Bioeng. Biotechnol., 3(211).
    b) Johnson, L. M. & Samuel Gellman, H. (2013). α-Helix Mimicry with α/β-Peptides. Methods Enzymol., 523, 407-429.
    c) Natasha Burgess, C., Thomas Sharp, H., Franziska Thomas, Christopher Wood, W., Andrew Thomson, R., et al. (2015). Modular Design of Self-assembling Peptide-based Nanotubes. J. Am. Chem. Soc., 137(33), 10554-10562.
    d) Pester, O., Barrett, P. J., Hornburg, D., Hornburg, P., et al. (2013). The backbone dynamics of the amyloid precursor protein transmembrane helix provides a rationale for the sequential cleavage mechanism of γ-secretase. J Am Chem Soc., 135(4), 1317-1329.
28. Derek Lowe, Gamma-Secretase Inhibitors: The Wrong Way Around?
29. Spires-Jones, T. L. & Bradley Hyman, T. (2014). The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease. Neuron, 82(4), 756-771.
30. Welling, M. W., Nabuurs, R. J. & Louise van der Weerd (2015). Potential role of antimicrobial peptides in the early onset of Alzheimer’s disease. Alzheimer’s & Dementia, 11(1), 51-57.
31. a) Abhisek Mukherjee, Diego Morales-Scheihing, Peter Butler, C. & Claudio Soto (2015). Type 2 diabetes as a protein misfolding disease. Trends in Molecular Medicine, 21(7), 439-449.
    b) Protein
32. Teng, P., Shi, Y., Sang, P. & Cai, J. (2016). γ-AApeptides as a New Class of Peptidomimetics. Chem. Eur. J., 22(16), 5458-5466.
33. Natalia Molchanova, Paul Hansen, R. & Henrik Franzyk (2017). Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs. Molecules, 22(9), 1430.
34. Hilal Lashueland, A. & Peter Lansbury, T. Jr. (2006). Are amyloid diseases caused by protein aggregates thatmimic bacterial pore-forming toxins? Quarterly Reviews of Biophysics, 39(2), 167-201.
35. Olivia Berthoumieu, Peter Faller & Andrew Doig, J. (2015). Inhibitors Of Amyloid Beta Peptide Aggregation. Toward New Drugs Against Alzheimer’s Disease. Alzheimer & Dimentia, 11(7), 352-353.
36. Ehud Gazit.
37. Róisín McManus, M. & Michael Heneka, T. (2017). Role of neuroinflammation in neurodegeneration: new insights. Alzheimer's Research & Therapy, 9(1), 14.
38. Subramanian Vivekanandan, Jeffrey Brender, R., Shirley Lee, Y. & Ayyalusamy Ramamoorthy (2011). A Partially Folded Structure of Amyloid-Beta (1-40) in an Aqueous Environment. Biochem Biophys Res Commun., 411(2), 312-316.
39. Hiroyuki Arai, Lee, V. M., Laszlo Otvos, Jr., Barry Greenberg, D., David Lowery, E., et al. (1990). Defined neurofilament, tau and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques. Proc. Natl. Acad. Sci., 87(6), 2249-2253.
40. Siegmund Reissmann (2014). Cell penetration: Scope and limitations by the application of cell-penetrating peptides. Journal of Peptide Science, 20(10), 760-784.
41. Kasza Ágnes, Hunya Ákos, Frank Zsuzsa, Fülöp Ferenc, Török Zsolt, et al. Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer’s Disease. Journal of Alzheimer's Disease, 53(2), 557-571.
42. Inbal Lapidot, Amnon Albec, Gary Gellerman, Shimon Shatzmiller & Flavio Grynszpan (2015). 1,4-Dihydropyridine Cationic Peptidomimetics with Antibacterial Activity. Int J Pept Res Ther., 21(3), 243-247.
43. Ananda Prasad Sen, Patricia Boksa & R6mi Quirion (1993). Brain calcium channel related dihydropyridine and phenylalkylamine binding sites in Alzheimer's, Parkinson's and Huntington's diseases. Brain Research, 611(2), 216-221.
44. Daniel Paris, Corbin Bachmeier, Nikunj Patel, Amita Quadros, Claude-Henry Volmar, et al. (2011). Selective Antihypertensive Dihydropyridines Lower Aβ Accumulation by Targeting both the Production and the Clearance of Aβ across the Blood-Brain Barrier. Molmed., 17(3-4), 149-162.
45. Nimmrich, V. & Eckert, A. (2013). Calcium channel blockers and dementia. British Journal of Pharmacology, 169(6), 1203-1210.
46. Sylvie Diochot, Sylvain Richard, Michel Baldy-Moulinie, Joël Nargeot & Jean Valmier (1995). Dihydropyridines, phenylalkylamines and benzothiazepines block N-, P/Q- and R-type calcium currents. Pflügers Arch., 431(1), 10-19.
47. Ranjit, K., Rao, G. K. & Pai, P. N. S. (2010). Synthesis and Biological Evaluation of N1-[(3z)-5-Substituted-2-Oxo-1, 2-Dihydro-3H-Indol-3-Ylidene]-5H-Dibenzo [b,f] Azepine-5-Carbohydrazides. International Journal of Biological Chemistry, 4(1), 19-26.
48. Richard Olson, E. & Charles Albright, F. (2008). Recent Progress in the Medicinal Chemistry of -Secretase Inhibitors. Current Topics in Medicinal Chemistry, 8(1), 17-33.
49. Upending Alzheimer’s Theory
50. Dietmar Seiffert, Jodi Bradley, D., Cynthia Rominger, M., David Rominger, H., Fude Yang, et al. (2000). Presenilin-1 and -2 Are Molecular Targets for g-Secretase Inhibitors. The Journal Of Biological Chemistry, 275(44), 34086-34091.
51. Lanz, T. A., Hosley, J. D., Adams, W. J. & Merchant, K. M. (2004). Studies of Aβ pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-di hydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575). J. Pharmacol. Exp. Ther., 309(1), 49-55.
52. Lynn Hyde, A., Nansie McHugh, A., Joseph Chen, Qi Zhang, Denise Manfra, et al. (2006). Studies to Investigate the in Vivo Therapeutic Window of the g-Secretase Inhibitor N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d] azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 Mouse. The Journal Of Pharmacology And Experimental Therapeutics, 319(3), 1133-1143.
53. Scott Mayer, C., Anthony Kreft, F., Boyd Harrison, Magid Abou-Gharbia, Madelene Antane, et al. (2008). Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease. J. Med. Chem., 51(23), 7348-7351.
54. Pomara, N. (2013). Semagacestat for treatment of Alzheimer's disease. N Engl J Med., 369(17), 1661.
55. Ting Li, Yunhong Huang, Shiyi Jin, Liang Ye, Na Rong, et al. (2012). γ-Secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment. J. Neurochem., 121(2), 277-286.
56. Galina Zats, M., Marina Kovaliov, Amnon Albeck & Shimon Shatzmiller (2015). Antimicrobial benzodiazepine-based short cationic peptidomimetics. J Pept Sci., 21(6), 512-519.
57. Abdul Fauq, H., Katherine Simpson, Ghulam Maharvi, M., Todd Golde & Pritam Das (2007). A multigram chemical synthesis of the γ-secretase inhibitor LY411575 and its diastereoisomers. Bioorg Med Chem Lett., 17(22), 6392-6395.
58. Joseph Milano, Jenny McKay, Claude Dagenais, Linda Foster-Brown, Francois Pognan, et al. (2004). Modulation of Notch Processing by g-Secretase Inhibitors Causes Intestinal Goblet Cell Metaplasia and Induction of Genes Known to Specify Gut Secretory Lineage Differentiation. Toxicological Sciences, 82(1), 341-358.
59. Phillips, L. K. & Horowitz, M. (2006). Amylin. Curr. Opin. Endocrinol. Diabetes, 13(2), 191-198.