Can Small Molecule Inhibitors of Glutaminyl Cyclase Be Used as a Therapeutic for Alzheimer'S Disease?

Abstract

Alzheimer's disease (AD) is a multifactorial and socioeconomically burdensome disease. In view of the failures of anti-AD candidates, we should try to rethink what we did before and what we should do next, in part at least. Research shows that the more neurotoxic factor, pyroglutamate-Aβs, and the more important inflammatory mediators, pyroglutamate-CCL2, both contribute to the initiation of AD specifically and the generation of N-terminal intramolecular cyclization catalyzed by glutaminyl cyclase quality control, the over-expression of which correlates positively with the severity of AD. Subsequently, lowering pyroglutamate-Aβs and pyroglutamate-CCL2 levels by quality control inhibition using small molecule inhibitors could be expected as an amazing strategy for the prevention and treatment of AD. Alzheimer's disease (AD) is a systematically chronic neurodegenerative disease characterized by diminution of cognitive function, memory, neurobehavioral manifestations, social withdrawal and other behavioral symptoms. AD is the most common cause of dementia in aging and accounts for 60-80% of all cases. The prevalence of AD has increased dramatically over the past decade and is expected to become even worse in the future owing to increased life expectancy. Unfortunately, we have almost no idea about the exact pathology of this multifactorial disease, and there is no cure, at least no disease modifying agents, for this socioeconomically burdensome disease. For these reasons, demand for development of appropriate prevention and/or treatment options for AD will continue to grow rapidly.As one of the hallmarks, extracellular amyloid plaques contribute to the death of neurons and development of AD. β-Amyloid (Aβ) pathology is well documented, and the Aβ cascade hypothesis has been one of the main hypotheses. However, the fact is no candidate targeting Aβ pathology directly has passed through clinical trials including the failure of Lilly's solanezumab and Merck's verubecestat. Obviously, the development of anti-AD agents is a world challenge now. We cannot judge that the amyloid cascade hypothesis is flawed even now, but is Aβ aggregate the reasonable target for the discovery of anti-AD agents? Do we have any 'misunderstanding' about the AD pathology? What is the problem with the development strategy we use? Maybe it is the time for us to change our chair and rethink in part at least what we saw, what we did, what we learned and what we should do next.Many studies confirm that the formation of Aβ plaques, mainly composed of Aβ 42 and Aβ 40 , has no direct effects on the development of neurodegeneration and other clinical AD symptoms. These plaques can be detected in both AD brains and normal brains. What is the pathological difference between these two types of brain? In recent years, a variety of N-truncated Aβs have been identified only in AD brains including pyroglutamate-Aβs (pE-Aβs), which are the generations of Aβs undergoing N-terminal truncation by two or ten amino acids and following cyclization of resulting N-te...

Benzimidazole and Benzoxazole Derivatives Against Alzheimer's Disease

“…In addition, QC inhibitors are known to effectively reduce the levels of Aβ N3pE and Aβ plaques in the brain, improving memory deficits in AD mice [96–97] . These findings support QC inhibition as a valid therapeutic strategy for AD [98–99] . Manh et al.…”

“…[96][97] These findings support QC inhibition as a valid therapeutic strategy for AD. [98][99] Manh et al investigated new classes of QC inhibitors designed using bioisostere-based, pharmacophore-based and structure-based approaches. Main pharmacophores: it can be classified as zinc-binding groups (pharmacophore A), hydrogen-bonding donors (pharmacophore B), or phenyl groups (pharmacophore C).…”

Functions of glutaminyl cyclase and its isoform in diseases

“…Pyroglutamylated Ab peptides (AbpEs) are found in selfaggregated Ab peptides and act as initiators of Ab accumulation, favoring plaque seeding [115,116]. AbpE is only found in AD brains and constitutes approximately 50% of the total Ab [117], so the level of AbpE has been treated as a potential biomarker of AD [118]. AbpE is upstream of the neurotoxic amyloid cascade, triggering neurodegeneration and enhancing AD pathology [119][120][121].…”

Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer’s Agents by Structure-Based Design

“…It has also been reported that small-molecule inhibitors of QC efficiently reduced the brain levels of pE-Aβ and Aβ plaques and improved memory deficits in AD mice . These studies suggested that inhibition of brain QC activity may bring about beneficial effects for AD patients. , Several research groups have developed QC inhibitors that are based on imidazole ( 1 ) and benzimidazole core structures ( 2 , 3 ) , (Figure ). The most prominent candidate is PQ912 ( 3 ), developed by Probiodrug, which showed improvement in synaptic and neurological functions in AD patients without significant toxicity in clinical trials. , More recently, Rubinsztein and colleagues introduced an N -methyltriazole-based inhibitor ( 4 , SEN177 ), which was discovered through three-dimensional (3D)-pharmacophore model-based in silico methods .…”

“…22 These studies suggested that inhibition of brain QC activity may bring about beneficial effects for AD patients. 25,26 Several research groups have developed QC inhibitors that are based on imidazole (1) 27 and benzimidazole core structures (2, 3) 28,29 (Figure 1). The most prominent candidate is PQ912 (3), developed by Probiodrug, which showed improvement in synaptic and neurological functions in AD patients without significant toxicity in clinical trials.…”