*2.1.2.3.1 Gamma secretase*

Inhibitors of BACE1 and gamma secretase have thus far showed limited Aβ clearance in clinical trials, even after demonstration of excellent inhibition in preclinical animal models [40]. Studies into gamma secretase found that it was the last step in Aβ fragment generation and an ideal target to prevent the build-up of fragments and formation of plaques [41]. Semagacestat was identified as potential drug candidate for clinical trials in decreasing Aβ levels, only after Phase III in the IDENTITY trials was it found to have adverse effects on Notch signalling [42]. Identified as a drug with a higher selectivity for APP over Notch in preclinical studies, Avagacestat was another gamma secretase inhibitor that showed similar effects to Semagacestat forcing the discontinuation of the trials due to adverse dose-limiting effects [43]. The adverse effects and lack of efficacy had quashed further research into gamma secretase inhibitors; however, a new look into gamma secretase as a target has identified that it is available for modulation, specifically altering the cleavage site of the enzyme. NGP 555 is a promising SME gamma secretase modulator that has showed promising results *in vivo,* significantly lowering levels of Aβ42 through a shift of cleavage site in gamma secretase [44].

#### *2.1.2.3.2 Alpha secretases*

Alpha secretase as a therapeutic target for AD offers a novel approach of upregulating cleavage of APP rather than preventing it. By cleaving APP within the Aβ domain, alpha secretase prevents the generation of Aβ fragments instead releasing non-toxic p3 peptide following gamma secretase cleavage [45]. Modulation of alpha secretase is expected to increase its activity and reduce levels of Aβ, potentially increasing the levels of a neuroprotective product of alpha secretase cleavage of APP, sAPPα [46]. Alpha secretases belong to the 'a disintegrin and metalloprotease' (ADAM) family, which are found to play roles in cell adhesion, migration, proteolysis and signalling [47]. ADAM10 was found to be the alpha secretase relevant to APP cleavage in neurons, making it the target of modulation in AD [48]. Two therapeutics that have undergone clinical trials showing potential as alpha secretases enhancers are etazolate (EHT-0202) and bryostatin-1. Both stimulate alpha secretase to increase generation of sAPPα [49]. The potential of alpha secretase enhancers as a therapeutic for AD is likely. However, studies into the effects of enhancers on the other substrates of ADAM10 are required to identify any possible adverse effects [50].

#### *2.1.2.3.3 BACE1*

Targeting BACE1 for therapeutic development in AD is ideal, as it is the determining step in the generation of Aβ fragments. Inhibition of BACE1 has shown to decrease levels of Aβ plaques. Studies in mouse models have proven that by removing BACE1 there is no generation of Aβ fragments, and subsequently no neurodegeneration and loss in cognitive abilities [51].

Since it was discovered to play a role in AD in 1999, BACE1 has been thoroughly researched as a potential target for AD. BACE1 has been an elusive target for inhibitors, its location in the brain, size of the active site, and similarity to other aspartic proteases making it difficult for the ideal therapeutic to be developed [52]. Initial inhibitors of BACE1 were non-cleavable peptide-based analogues, designed on the amino acid sequence of APP, which showed excellent inhibitory effects on BACE1. However, the size was too large to exhibit *in vivo* benefits, although ideal for the active site [53]. The development of SMEs for BACE1 renewed hope in the use of the aspartic protease as a target, hoping to increase blood–brain barrier (BBB) penetration and bioavailability that were identified as issues with the first-generation BACE1 inhibitors. From there, the hunt for a BACE1 inhibitor began with multiple classes of inhibitors being developed in an attempt to find the ideal therapeutic.

In a similar pattern to other amyloid therapies, BACE1 inhibitors in other trials were halted or discontinued due to lack of efficacy or off-target effects. Only two BACE1 inhibitors were in the 2019 cohort of clinical trials: CNP520, discontinued in July 2019 due to worsening of cognitive function, and E2609, discontinued in September 2019 due to unfavourable risk–benefit ratio [54, 55]. Both compounds joining the list of lessons learnt from BACE1 inhibitors, along with Lanabecestat, Atabecestat and Verubecestat. All of which proved excellent in reducing Aβ; however, translation into clinical trials was not as smooth, lacking efficacy or displaying off-target effects [56].

#### **2.2 Improving therapeutics or target choice**

With no current curative treatments for AD available, previous cohorts of clinical trials are missing something vital. The types of therapeutics used and targets

**27**

half-life [58].

future.

**3.1 What are peptides?**

infectives and growth factors [58].

*An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease*

available explained above show that therapeutic discovery is not a simple task, particularly in a disease as complex as AD. The ideal neuroprotective therapeutic for combating AD is one that targets the initiating steps of amyloid development with high specificity and potency, while not disrupting other biological processes. An attractive initiating step of amyloid development is BACE1, discussed above as a promising target to prevent the generation of Aβ fragments responsible for the activation of microglia and subsequent development of neurodegeneration. Previous attempts at inhibiting BACE1 have shown mixed and unfavourable

responses of properties such as specificity, bioavailability and efficacy. Both biologicals and SMEs cannot fill the requirements of such a specific therapeutic, requiring a molecule that has the ideal properties of both. Such a molecule is already being explored in therapeutic development for AD although it is still in its infancy as a class of therapeutic molecule for AD. Peptides are becoming more attractive as a therapeutic to target BACE1 with new technology altering their structure to better fit the required properties. Such research promises to pave new and exciting ways to developing refined peptide inhibitors of BACE1 with high efficacy and specificity, and thus prepare novel reagents for the prophylactic treatment of AD in the near

Peptides are small molecular biologicals that play a major role in the body as signalling molecules. Naturally occurring peptides in humans are commonly called hormones, acting as messengers utilising the blood stream and other extracellular spaces to regulate the many biological processes that keep us going [57]. Two of the most well-known peptides are glucagon and insulin, both playing large roles in homeostasis of blood-glucose levels. These hormones act on blood-glucose levels by targeting accessory organs and stimulating glucose production or glycogen storage, respectively. The action of glucose and insulin is a classic example of how peptides work in the body with high specificity and rapid onset of effect. Although commonly linked to hormones, peptides are also used as neurotransmitters, anti-

Peptides range in length from 10 to 50 amino acids long, and can have a mass of up to 5 kDa, putting them between SMEs and proteins in terms of size and weight. *In vivo*, natural peptides are highly efficacious and selective with limited off-target effects, transient at most for those that exist [59]. Their ability to act as signalling molecules both extracellularly and intracellularly displays the range of therapeutic opportunity that peptides exhibit. Following the discovery of peptides playing large roles in homeostasis in the body, research turned towards identifying and isolating certain peptides that were linked to diseases. To continue with the example of insulin, the development of insulin as a therapeutic comes from the identification of individuals lacking a "pancreatic secretion" in the early 1900s, where insulin was isolated from the pancreas of stray dogs and calves and used to treat a child with type I diabetes [57]. This discovery only fuelled the fire for further discovery and isolation of other natural peptides that were found to be involved in diseases, leading to the identification of over 7000 naturally occurring peptides. Although identified, not all can be used directly as a therapeutic due to unbeneficial properties such as poor bioavailability and short

*DOI: http://dx.doi.org/10.5772/intechopen.91065*

**3. New outlook for Alzheimer's disease**

*An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.91065*

available explained above show that therapeutic discovery is not a simple task, particularly in a disease as complex as AD. The ideal neuroprotective therapeutic for combating AD is one that targets the initiating steps of amyloid development with high specificity and potency, while not disrupting other biological processes. An attractive initiating step of amyloid development is BACE1, discussed above as a promising target to prevent the generation of Aβ fragments responsible for the activation of microglia and subsequent development of neurodegeneration. Previous attempts at inhibiting BACE1 have shown mixed and unfavourable responses of properties such as specificity, bioavailability and efficacy. Both biologicals and SMEs cannot fill the requirements of such a specific therapeutic, requiring a molecule that has the ideal properties of both. Such a molecule is already being explored in therapeutic development for AD although it is still in its infancy as a class of therapeutic molecule for AD. Peptides are becoming more attractive as a therapeutic to target BACE1 with new technology altering their structure to better fit the required properties. Such research promises to pave new and exciting ways to developing refined peptide inhibitors of BACE1 with high efficacy and specificity, and thus prepare novel reagents for the prophylactic treatment of AD in the near future.
