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10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
66h
66i
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316
Table10.4 (Continued)
Inhibitor
hOGA K
(nM)
60 ± 10
a
hHexB K
i
(μM)
d
b
hHexB/
i
hOGA
150 ± 50 2500 6.18 0.06
c
pK
a
Fraction
protonated
at pH 7.4
1000 ± 200d4200 ± 1525 4200 5.33 0.01
a) Determined with the Morrison Ki fit if values are below 5 mM;
b) Determined using Dixon plot analysis;
c) Selectivity ratios indicating favored selectivity for hOGA over hHexB;
d) Determined using Michaelis–Menten inhibition analysis. Source: Adapted from Cekic etal.[40].
Ki values are comparable to the enzyme concentration being studied, and reached
some remarkable results. The first one is related to Thiamet-G, in which K
nM instead of the 21 nM given previously when evaluated by the Michaelis–
2.1
value is
i
Menten method[43]. The first picomolar hOGA inhibitor discovered is LSO, exhibit-
= 510 ± 50 pM and a selectivity of 3300 for hOGA over β-hexosaminidase. The
ing K
i
size of the chain is also important for binding. Compounds embodying N-methyl,
N-ethyl, N-propyl, or N-allyl groups have K
compound with the N-butyl group suffered 100-fold decrease of activity (K
in the range of 2.0–3.2 nM, while the
i
= 350 nM).
i
The side chains with two and three carbon atoms are, indeed, the most important to
increase selectivity for hOGA inhibition over β-hexosaminidase inhibition, as clearly
deduced from selectivity values given in Table10.5. Interestingly, compounds 8a
Table10.5 Inhibition data of hOGA and lysosomal hexosaminidases (HexA/B) by
GlcNAcstatins A-G, PUGNAC, Thiamet-G, and selectivity for hOGA[53, 54].
Compound hOGA (Ki nM) HexA/B(GH20) (Ki) Selectivity GH20/hOGA References
GlcNAcstatin 4.4 ± 0.1 550 ± 10 nM 164 [58]
GlcNAcstatin A 4.3
± 0.2 0.55 ± 0.05 nM Not selective [58]
GlcNAcstatin B 0.42 ± 0.06 0.17 ± 0.05 nM Not selective [58]
GlcNAcstatin D 0.74 ± 0.09 2.7 ± 0.4 nM 4 [58]
GlcNAcstatin E 8500 ± 300 1100 ± 100 nM Not selective [58]
GlcNAcstatin F 11.2 ± 1.4 11.0 ± 0.6 μM 1000 [59]
GlcNAcstatin G 4.1 ± 0.7 >3700 >900 000 [59]
GlcNAcstatin H 2.6 ± 0.3 100±30 35 000 [59]
PUGNAc 35 ± 6 25 ± 2.5 Not selective [59]
Thiamet-G 21 750 35 000 [43, 59]
10.2 O-GlcNAc Transferase (OGT) and O-GlcNAc Hydrolase (OGA) in Neurodegeneration
and 8d have some selectivity for hOGA, which is not the case for NAG-thiazoline 4a,
a molecule with a similar size[39, 40]. This result reinforces the key role of the amino
group in improving inhibitor selectivity over human β-hexosaminidase.
The contribution of inhibitor pK
the results obtained for the fluorinated inhibitors. pK
13
determined by
C nuclear magnetic resonance (NMR) titration[40, 66]. The correla-
tion obtained by plotting pK
for the potency of the inhibition stood out from
a
of their conjugate acids was
a
with the corresponding logKi value suggested that pKa
a
dominates the effect of inhibitor binding to the active site, as compared to the steric
effect resulting from increased fluor substitution. The key role of pK
in binding may
a
be due to optimization of hydrogen bond strength or favoring inhibitor protonated
form. Quantitative methods carried out by Cekic et al. [40] demonstrated that,
through their formal positive charge at physiological pH, these compounds have
favorable interactions with the active site, only partly carried out within the transition state for the natural 2-acyl substrates, showing that Thiamet-G and analogs
embodying an alkylamino group are tight-binding transition state analogs for
hOGA. This work gave, in 2016, a new insight into the catalytic mechanism of hOGA
and provided a new picomolar inhibitor representative of this compound series[40].
More recently, in 2019, further studies on this family of compounds were reported,
inspired by Thiamet-G, which is well tolerated over extended treatment periods.
However, it was found that it has a high polar surface (105 Å), resulting in a low diffusion rate into and out of the CNS from systemic circulation[67]. Aiming to obtain
better clinical candidates, the collaboration of the companies Alectos Therapeutics
Inc, Merck, and Pharmaron Beijing resulted in the generation of MK8719 (86, see
Table10.6, Figure10.7), the Thiamet G analog, which is a highly potent (K
= 7.9 nM
i
for hOGA) and selective OGA inhibitor with excellent CNS penetration, and has
been advanced to phase I clinical trials[68]. It stood out of a small library of 49
Thiamet G analogs generated by hypothesizing that modification of molecule polar
substituents would result in a reduced topological polar surface area (TPSA) and
consequently in a greater and faster distribution of the compound into CNS[67].
Focusing on the carbohydrate moiety hydroxy groups and the thiazolinesubstituted amino group, a series of analogs with structure type A (Figure10.7) was
synthesized and tested[67]. Regioselective methylation of hydroxy groups or its
replacement by hydrogen or by fluor atoms afforded compounds with lower
TPSA. However, the potency of hOGA inhibition varied according to inhibitor structure and stereochemistry (Table 10.3). No inhibition occurred when OH-4′ was
absent, as shown for compounds 70, 74, and 77, indicating that this group is important for activity. Nonetheless, some structural changes are tolerated without complete loss of activity, e.g. the replacement of the primary hydroxyl group by hydrogen
(compound 73) or by fluor (compound 76), and that of OH-3′ by fluor (compounds
78 and 79). The absolute configuration was shown to be important for hOGA inhibition, together with the replacement of the N-ethyl group by the N-methyl group. By
combining monofluorination of the primary alcohol with a 7-fluoro substituent in
compound 82, the pharmacokinetic properties were improved when compared to
the monofluorinated compound 81, as well as the selectivity over hexosaminidase
inhibition, the TPSA value and the apparent permeability.
317
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
65 (Thiamet-G)
69
70
71
72
73
74
75
76
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318
Table10.6 Data obtained in assays to determine the inhibition of hOGA, the
concentration required for EC
values for elevation of all protein O-GlcNAc levels, the
50
selectivity over hexosaminidases, calculated TPSA, and apparent permeability.
Compound Nr/Structure
hOGA Ki
(nM)
rOGA cell EC50
(nM)
hHEX Ki
(nM) TPSA (Å)
Papp (10−6
cm s−1)
0.41 13.5 >10 000 105 <1.0
190 — — 94 —
>3000 — — 91 —
270 — >10 000 91 —
5.5 36.7 3600 93 1.1
69 — — 84 —
>3000 — — 86 7.0
44 364 — 84 2.6
20 176 — 84 6.1
(Continued)
10.2 O-GlcNAc Transferase (OGT) and O-GlcNAc Hydrolase (OGA) in Neurodegeneration
77
78
79
80
81
82
83
84
Table10.6 (Continued)
319
Compound Nr/Structure
a
hOGA Ki
(nM)
rOGA cell EC50
(nM)
hHEX Ki
(nM) TPSA (Å)
Papp (10−6
cm s−1)
>3000 — >10 000 84 —
29 443 >10 000 84 2.7
0.53 10.6 >10 000 84 —
9.0 177 1600 69 6.8
0.55 34.4 790 83 5.3
35 328 >10 000 61 26
>3000 — >10 000 47 31
28 — >10 000 47 31
(Continued)
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
85
86 (MK8719)
(a) (b)
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320
Table10.6 (Continued)
Compound Nr/Structure
hOGA Ki
(nM)
rOGA cell EC50
(nM)
hHEX Ki
(nM) TPSA (Å)
Papp (10−6
cm s−1)
5.3 — >10 000 61 24
7.9 52.7 >10 000 80 6.4
a) Absolute configuration at position 6was not assigned. Source: Adapted from Selnick etal.[67].
The high permeability found for the difluorinated compound 82 inspired further
research with structures type B (Figure10.7) and this scaffold was investigated for
modifications of the amino group substituent. Compound 83, bearing a dimethylamino group, does not inhibit hOGA, while compounds 84–86, with a monosubstituted amino group, have restored this activity. Nonetheless, compound 86
(MK8719) is the one showing a good balance of hOGA potency, apparent permeability, and selectivity vs. hHEX.
The collection of Papp data for 49 compounds tested was compared to the calculated TPSA values and a reasonable correlation was found, corroborating the
hypothesis based on reducing TPSA to obtain compounds with higher permeability
Figure10.7 Structure of 5-substituted methyl tetrahydropyranothiazole compounds
type (a) and of 5-difluoromethyl tetrahydropyranothiazoles type (b) studied by Selnick
etal.[67] to illustrate TPSA/permeability and structure/activity relationships. Source:
Adapted from Selnick etal.[67].
10.2 O-GlcNAc Transferase (OGT) and O-GlcNAc Hydrolase (OGA) in Neurodegeneration
than that of Thiamet-G. Interestingly, some of the new structures were able to
increase protein O-GlcNAc levels (Table10.6).
As compound bioavailability was moderate to very good, compound differentiation was made through pharmacodynamic effects. For the most promising compounds exhibiting potent hOGA inhibition (K
6
measurable permeability (>2 × 10
cm s1), as well as for the 5-difluoromethyl deriv-
<20 nM), EC50 <200 nM, and
i
atives 83–86, the pharmacodynamic effect of OGA inhibition in the CNS was evaluated by measuring the time-dependent accumulation of total O-GlcNAc protein in
rat brain after a single oral dose of inhibitor and data was collected after 8 and
24 hours of dose intake[67]. Inhibitor concentration in plasma and in brain homogenate was also evaluated to compare distributional delay in brain exposure (Table10.2).
Compounds 80 and 81 have both a greater effect at eight hours than compound 65
(Thiamet-G) but 81 shows an interesting high level of O-GlcNAc protein for a low
brain exposure when compared to compounds 80 and 65. Compounds 84 and 85
have also demonstrated significant effects and a good brain exposure[67].
In conclusion, the potent and selective hOGA inhibitors, exhibiting biodistribution to the CNS, also afford increased O-GlcNAc protein levels. Among all tested
compounds, 86 (MK8719) stood out with a balanced brain and plasma exposure and
a greater efficacy over Thiamet-G, possibly resulting from its greater brain exposure,
as the brain AUC value (area under the plot of inhibitor concentration in the brain
–1
vs. time after dose intake) for a dose of 10 mg kg
–1
24 hours was 9.64 nM h g
, while that of Thiamet-G was only 1.14 nM h g–1[67].
of 86, at time points 1, 4, 8, 12, and
The production of MK8719 (86) was carried out starting from compound 65
(Thiamet-G) (Scheme10.11). Boc protection of the amino group was followed by
321
Scheme 10.11 Synthesis of MK8719[67]. Reagents/solvent and yield: (a) Boc2O, iPr2NEt,
DMF/MeOH, 64%; (b)TBDMSCl, imidazole, 76%; (c) BzCl, DMAP, 71%; (d) AcCl, MeOH, 90%; (e)
Dess-Martin periodinane reagent (DMP), pyridine, DCM, 0 °C–rt; (f) DAST, DCM, 40%; (g)
K
, MeOH, 92%; (h) TFA, DCM, 95%.
2CO3
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
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322
regioselective protection of the primary alcohol by reaction with tercbutyldimethylsilyl chloride (TBDMSCl). Benzoylation of the free hydroxy groups of
88 followed by cleavage of the silyl group afforded compound 89, whose primary
alcohol was oxidized to aldehyde with Dess–Martin periodinane, further reacting
with DAST to give compound 90 in 40% yield over the two steps. Deprotection with
potassium carbonate to generate the hydroxy groups and with TFA for Boc cleavage
afforded MK8719 (86) in 10.9% overall yield from Thiamet-G[67].
The hypothesis whereby increasing O-GlcNAc levels in Tau hinders Tau aggregation was recently investigated by Wang etal.[69] by applying MK8719 invivo in a
rTg4510mouse model of tauopathy. As O-GlcNAcylation levels are reduced in AD
brains, and the decrease of Tau O-GlcNAc levels is correlated with increased tau
hyperphosphorylation, resulting in the formation of insoluble Tau aggregates, inhibition of OGA by MK8719was envisioned as a strategy to attenuate Tau aggregation.
It was found that oral administration of MK8719 to a rTg4510 mouse model of
human tauopathy results in a significant increase of brain O-GlcNAc levels and
reduction of pathological Tau, accompanied by attenuation of brain atrophy with
reduction of forebrain volume loss as observed by volumetric magnetic resonance
imaging. Although these are encouraging results for the usefulness of OGA inhibitors in reducing Tau pathology, it is crucial to understand the physiological and toxicological consequences of O-GlcNAc elevation in vivo, as there are many
O-GlcNAcylated proteins that may also be influenced by OGA inhibition[69].
10.3 GalNAc in Neurodegeneration
In 2017, the relationship between AD and O-GalNAcylation was reported in several
studies. Akasaka-Manya etal.[34] used real-time PCR to analyze the expression of
human brain GalNAc-transferases (GalNAc-Ts), which transfer GalNAc from UDPGalNAc to Ser or Thr residues, and showed that the expression of several GalNAc-Ts
was altered with sporadic AD progression. To evaluate the impact of GalNAc-Ts
overexpression on Aβ production, GalNAc-T1, GalNAc-T4, and GalNAc-T6 were
transfected into HEK293T cells. Briefly, while GalNAc-T1 and GalNAc-T4 reduced
Aβ1–40 formation, GalNAc-T6 reduced the production of both Aβ1–40 and Aβ1–42.
From all three GalNAc-Ts, GalNAc transferase activity on APP was more relevant
for GalNAc-T6, suggesting that enhanced O-glycosylation on APP by
GalNAc-T6inhibits Aβ production. GalNAc-T1, GalNAc-T4, and GalNAc-T6were
transfected into HEK293T cells to overexpress them and determine their effect on
Aβ production. Transfection of GalNAc-T6 significantly reduced the generation of
both Aβ1–40 and Aβ1–42
formation. Although the three GalNAc-Ts showed enzymatic activity on soluble
APP, the activity of GalNAc-T6 on APP was the most prominent one. The expression
of α-secretase and BACE1was slightly altered in the transfected cells, but the activity of both secretases was not significantly altered. Their data suggested that excess
O-glycosylation on APP by GalNAc-T6 inhibits Aβ production [34]. In 2020
Akasaka-Manya and Manya[70] reported that the reduced Aβ generation by coexpression of APP and GalNAc-T6 resulted from a decrease of β-cleavage, while the
expression level of membrane-bound APP did not change. As possible explanations
while GalNAc-T1 and GalNAc-T4 only reduced Aβ1–40
,
10.3 GalNAc in Neurodegeneration
for the β-cleavage decrease, they suggest that either glycosylated APP is not transported to the location for β-cleavage, or BACE1 cannot approach glycosylated APP
resulting from conformational changes. However, the upregulation of GalNAc-T6
observed in AD brains and the protective effect of GalNAc-T6 acting against Aβ
generation remain contradictory, urging for further research to understand these
results[70].
An interesting study highlighting the role of O-GalNAcylation on the amyloidogenic
property of glycopeptides was carried out by Lin etal. in 2014[14]. The authors showed
that GalNAc α-O-linked to Ser135 residue of the prion peptide PrP(108–144), whose
structure suffers a coil-to-β conversion associating into amyloid fibrils, had a prominent effect on the conformation of the polypeptide chain and inhibited amyloidogenesis. They suggested that the acetamido group in the equatorial position of GalNAc
carbon 2 is important in the interaction between sugar and peptide, because the antiamyloidogenic effect was not found when the sugar α-linked to Ser135was galactose.
Another study by Liu etal. in 2017[71] has shown that by reducing GalNAc-T2
activity with its competitive inhibitor luteolin, a tetrahydroxyflavone, the generation of total Aβ, Aβ1–40
and Aβ1–42was reduced in a dose-dependent manner in
,
cells coexpressing APP and GalNAc-T2. GalNAc-T1, GalNAc-T3, and GalNAc-T13
transfer GalNAc to APP as well but only GalNAc-T3was also inhibited by luteolin.
They found that both sAPPα and sAPPβ were reduced, suggesting that the process
occurs prior to the intervention of secretases, and demonstrated that reduction of
Aβ production resulted from the decrease of APP O-GalNAcylation. In addition,
they have shown that the inhibitor luteolin also reduced Aβ production in the brain
of APP/PS1 transgenic mice.
GalNAc is a residue present in complex molecules, the GAGs and the PGs, which
together with proteins compose the cerebral extracellular matrix. Their accumulation surrounding certain neurons forms the perineuronal nets (PNNs) [72–75],
whose components are synthesized by neurons, astrocytes, and oligodendrocytes,
and form a unique environment. The major PNNs component is hyaluronan, a polysaccharide composed of disaccharide repeating units of glucuronic acid and GlcNAc.
It is the only PNN GAG that is not bound to sulfate nor to a core protein. Other components are chondroitin sulfate proteoglycans (CSPGs), where GAGs are linked to a
core protein and contain repeating units of disaccharides composed of an amino
sugar (GalNAc or GlcNAc) and galactose or a uronic acid, namely glucuronic or iduronic acid. PNNs also contain hyaluronan and PGs binding proteins[73]. PNNs function as a neuron physical barrier, also forming a polyanionic microenvironment
around neurons. They participate in brain signaling pathways and in synaptic plasticity and change from physiological to pathological conditions[73]. Baig etal.[72]
showed, in 2005, that there is substantial loss of GalNAc from PNN CSPGs from the
frontal cortex in AD, indicating a degradation of PNN composition around neurons
and certainly affecting PNN functions that depend on GalNAc containing CSPGs
side chains[72]. The authors concluded that further studies are required to characterize PNN degradation processes and their effects on AD. Indeed, further investigation on PNN has demonstrated its importance in controlling plasticity, regulating
axonal growth and regeneration, and in memory storage. Inspired by modulating
PNNs, either by targeting interactions with PNN core components or through PNN
digestion, new options emerge for drug development in AD therapy[75].
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324
10.4 Chitosan and Derivatives in AD Brain
Chitin is a linear polymer of β-(1→4) linked GlcNAc residues found in crustacean’s
exoskeletons and fungi’s cell walls. It is the second most abundant natural polymer
on earth and has been widely used in the field of biomaterials due to its nontoxic
nature, biocompatibility, and biodegradability[76]. From chitin deacetylation, CTS,
a linear polymer of β-(1→4) linked β--glucosamine (GlcN), can be obtained.
Chitosan oligosaccharides (COSs) are biodegradation products of CTS or chitin,
with low molecular weight and high-water solubility, due to their shorter chain
lengths and free amino groups, making them easily absorbed by the human intestine[77]. CTS, COS, and their derivatives also possess antioxidant, anti-HIV, antiinflammatory and neuroprotective effects[77].
Neuroinflammation results in oxidative stress in the synapses and mitochondria,
contributing to neuronal and vascular degeneration in AD brain. Water-soluble CTS
was found to have beneficial effects against the inflammatory response associated
with Aβ, which induces inflammation by the production of pro-inflammatory
cytokines tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) in the brain. The
secretion of both cytokines in human astrocytoma cells was induced by Aβ25–35
and interleukin-1β (IL-1β), a critical neurotoxic component in AD, the levels of
which are increased in AD patients[78]. Kim etal. showed that pretreatment with
water-soluble CTS (1
both TNF-α and IL-6. In addition, considering that Aβ25–35induces the production
of nitric oxide by regulating nitric-oxide synthase in neuroglial cells, and higher
levels of this enzyme surround Aβ and produce neurotoxicity in astrocytes, damaging AD brain, the authors[78] also showed that expression of nitric oxide synthase
is partially inhibited by treatment with water-soluble CTS. These experiments confirmed that the water-soluble CTS used has, indeed, regulatory effects on human
astrocytes.
Jiang etal.[79] evaluated the activities of N-acetyl COS (NA-COS) in neurodegeneration. The results of their work demonstrated that NA-COS significantly improved
learning and memory of AD rats. Furthermore, hematoxylin and eosin (HE) staining of brain tissue sections showed that NA-COS was able to diminish hippocampal
neurodegeneration induced by Aβ25–35, while the treatment of intrahippocampal
with NA-COS decreased hippocampal AChE and malondialdehyde levels, with an
increase in ACh concentrations. In addition, with NA-COS treatment, antioxidant
enzyme levels (superoxide dismutase and glutathione peroxidase) in rat’s hippocampus were also enhanced[79].
Recently, alendronate (ALN)-loaded CTS nanoparticles (CTS-ALN-NPs) for brain
delivery by a noninvasive intranasal route were investigated. CTS-ALN-NPs reduced
the peripheral side effects and released ALN directly into brain. The in vitro and
ex vivo release profiles revealed a sustained drug release through CTS-ALN-NPs
when compared to the pure drug solution. Furthermore, intranasal CTS-ALN-NPs
were evaluated against intracerebroventricular-streptozotocin (ICV-STZ), which
induces AD-like pathologies in mice[80]. The intranasal CTS-ALN-NP altered the
ICV-STZ-induced neurobehavioral, neurochemical, and histopathological changes
μg ml
1
and 10 μg ml1) significantly inhibited secretion of
10.5 Cholinesterase Inhibitors
in mice. The treatment of these mice with CTS-ALN-NPs resulted in a reduction of
the neuroinflammatory cytokines IL-6, IL-1β, and TNF-α levels in the hippocampus, which highlights the anti-inflammatory activity of ALN. The effect of ALN was
found to be more pronounced when administered in the form of CTS-NPs intranasally, which allowed the direct release of ALN into the brain, hence avoiding passage through the gastrointestinal tract[80].
The cholinergic neurotransmission mediated by ACh has a well-known role in
modulation of learning and memory[81]. Indeed, the attenuation of ACh levels due
to the aggravating activity of AChE and BChE enzymes significantly contributes to
cognitive disabilities[82]. AChE and BChE levels were increased in the hippocampus of mice that received ICV-STZ injections, accompanied by important reductions
in memory and learning abilities. In contrast, a drop in the levels of both ChEs was
noticed after treatment with CTS-ALN-NPs, revealing that ALN is capable of reversing deficits in cognitive and cholinergic functions[80]. Furthermore, the inhibition
of STZ-induced BACE-1 overexpression was observed in the hippocampus of mice
treated with a subdiabetogenic ICV-STZ followed by the intranasal administration
1
of CTS-ALN-NPs for 15 days (0.0352 mg kg
), along with reductions in Aβ1–42levels. Interestingly, CTS-ALN-NPs led to stronger reductions in BACE-1 and Aβ1–42
peptide levels when compared to an ALN pure solution. These results show that
CTS-ALN-NPs are capable of attenuating pathological changes observed in AD[80].
325
10.5 Cholinesterase Inhibitors
As previously referred, AD is a multifactorial neurodegenerative brain disorder, and
its exact pathophysiology is not yet entirely known. One of the variables that has a
direct link to AD is the cholinergic system, which directly contributes to regulation
and memory processes and, therefore, represents a target for AD drug design [83].
Early studies involving AD’s patients found an altered cholinergic activity, which
resulted in cognitive and functional symptoms[84]. The two major forms of ChEs, in
mammalian tissues, are AChE EC 3.1.1.7 and BChE EC 3.1.1.8. Both belong to the
group of Ser hydrolases and are responsible for the breakdown of the neurotransmitters ACh and butyrylcholine (BCh), respectively[85]. AChE is substrate specific in
nature and is found in high concentrations in the brain, while BChE is nonspecific
and is distributed throughout the body. Under normal conditions, ACh is dominantly
decomposed by AChE. Both enzymes exhibit different kinetic characteristics, depending on ACh concentrations. When ACh concentration is low, AChE’s activity is major,
whereas BChE presents higher activity when ACh concentration is elevated. In progressed AD, AChE in brain declines to 55–67% of normal values while BChE increases
to 120% of normal levels, indicating that BChE plays a critical role in ACh hydrolysis,
at a late stage of AD[83]. In fact, it has been reported that the specific inhibition of
BChE is important for raising ACh levels and improving cognition [86]. Hence,
designing selective, potent, and well-tolerated inhibitors of each ChE became a challenge for the scientific community, in order to determine which enzyme needs to be
targeted for maximum effect in treating AD. Currently, there are some approved ChE
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