Amyloid-β Peptide-specific DARPins as a Novel Class of Potential Therapeutics for Alzheimer Disease

Hanenberg, Michael; McAfoose, Jordan; Kulic, Luka; Welt, Tobias; Wirth, Fabian; Parizek, Petra; Strobel, Lisa; Cattepoel, Susann; Späni, Claudia; Derungs, Rebecca; Maier, Marcel; Plückthun, Andreas; Nitsch, Roger M.

doi:10.1074/jbc.m114.564013

Cited by 19 publications

(21 citation statements)

References 45 publications

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“…This is also true for ANK proteins [51]. One of the advantages of using DARPins is that they exhibit high affinity (in as low as picomolar concentrations) and high specificity to the target protein as well as being thermodynamically stable [66,67]. The high specificity is ascribed to their rigid interface arising from three repeated β-turns in the ANK repeats (166 residues) [56].…”

Section: Designed Ankyrin Repeat Proteins: Engineered Scaffold Proteimentioning

confidence: 99%

“…Furthermore, their potential to inhibit enzymes such as proteases, kinases and membrane proteins allosterically is vital for proper regulation and function of the body. Hanenberg et al demonstrated using mouse models DARPins' therapeutic potential in the treatment of Alzheimer's, a neurodegenerative disease characterized by short-term memory loss and even dementia [66]. Amyloid-β peptide (Aβ) -a crucial molecule involved in the inception and progression of Alzheimer's -was observed to be delayed from aggregating by binding specifically to DARPins and eventually neutralized and, ergo, prevented Aβ-mediated neurotoxicity in vitro.…”

Section: Designed Ankyrin Repeat Proteins: Engineered Scaffold Proteimentioning

confidence: 99%

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Ankyrins in human health and disease – an update of recent experimental findings

Chagula

Rechciński

Rudnicka

et al. 2020

aoms

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Ankyrins are adaptor molecules that in eukaryotic cells form complexes with ion channel proteins, cell adhesion and signalling molecules and components of the cytoskeleton. They play a pivotal role as scaffolding proteins, in the structural anchoring to the muscle membrane, in muscle development, neurogenesis and synapse formation. Dysfunction of ankyrins is implicated in numerous diseases such as hereditary spherocytosis, neurodegeneration of Purkinje cells, cardiac arrhythmia, Brugada syndrome, bipolar disorders and schizophrenia, congenital myopathies and congenital heart disease as well as cancers. Detecting either down-or over-expression of ankyrins and ergo their use as biomarkers can provide a new paradigm in the diagnosis of these diseases. This paper provides an outline of knowledge about the structure of ankyrins, and by making use of recent experimental research studies critically discusses their role in several health disorders. Moreover, therapeutic options utilizing engineered ankyrins, designed ankyrin repeat proteins (DARPins), are discussed.

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Section: Designed Ankyrin Repeat Proteins: Engineered Scaffold Proteimentioning

confidence: 99%

Section: Designed Ankyrin Repeat Proteins: Engineered Scaffold Proteimentioning

confidence: 99%

Ankyrins in human health and disease – an update of recent experimental findings

Chagula

Rechciński

Rudnicka

et al. 2020

aoms

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“…Mitochondrial membrane rupture caused by oxidative stress allows calcium to flow into the cytoplasm, activating calcium dependent proteases and increasing intracellular free radicals. Such further damage to mitochondrial function is expected to result in neuronal energy metabolism disorders and aggravation of neurological degenerative diseases (Choi et al, 2014b;Hanenberg et al, 2014). LA, a powerful antioxidant, can inhibit the generation of oxygen free radicals and thus can regulate GSH.…”

Section: Discussionmentioning

confidence: 99%

Effects and mechanism of lipoic acid on beta-amyloid-intoxicated C6 glioma cells

Xing

Qin

et al. 2015

Genet. Mol. Res.

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ABSTRACT. β-amyloid peptides (Aβs) can exert neurotoxic effects through induction of oxidative damage, whereas lipoic acid (LA), a powerful antioxidant, can alleviate oxidative damage. In this study, we explored the effect and mechanism of action of LA on beta-amyloidintoxicated C6 glioma cells. Cells were randomly divided into three groups: control (vehicle), Aβ, and LA + Aβ. The LA + Aβ group was treated with LA for 2 h, then both the Aβ-only and the LA + Aβ groups were incubated with 25 μM Aβ for 24 h. Cell viability was measured by the MTT method. Mitochondrial reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were detected by enzyme-linked immunosorbent assay (ELISA), and the GSH to GSSG ratio calculated. Real-time polymerase chain reaction and western blot analyses were used to detect MnSOD mRNA and protein, respectively. Aβ significantly inhibited C6 cell proliferation compared with the control group (P < 0.05). LA markedly increased cell viability compared with the Aβ group (P < 0.05). The increased GSSH and decreased GSH mitochondrial accumulation induced by Aβ was profoundly reversed by treatment with LA (P < 0.05). Aβ significantly reduced MnSOD expression compared to controls (P < 0.05), whereas LA pretreatment increased MnSOD expression compared with the Aβ-only group (P < 0.05); MnSOD protein levels showed similar patterns. These results suggest that LA might protect Aβ-intoxicated C6 glioma cells by alleviating oxidative damage, providing a new treatment strategy for neurodegenerative diseases.

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“…и обладающего стабильной структурой из Я-поворота и двух ά-спиралей. Обычно белки представлены 4-6 модулями с суммарной молекулярной массой от 14 до 21 кДа (молекулярная масса каждого 3,5 кДа) [30,31].…”

Section: применение альтернативных каркасных белков для радио-нуклиднunclassified

Alternative scaffolds in radionuclide diagnosis of malignancies

et al. 2019

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This review discusses a relatively new class of targeted molecules that is being actively studied for radionuclide diagnosis and treatment of malignancies. The full-size antibodies used so far have non-optimal pharmacological properties, slow distribution in the body, poor penetration into the tissue and kidney excretion, and high immunogenicity, which significantly complicates their use in clinical practice. Over the past decade, a new class of targeted molecules, called “non-immunoglobulin scaffolds” have become popular; they have all the requirements for optimal delivery of a radionuclide to tumor cells. Scaffolds usually are smaller in size in comparison with antibodies, but they are larger than peptides, and are characterized by high affinity and optimal biochemical, biophysical, biological, and economic features. The advantages of such proteins are their stable structure, good penetration into tissues, the possibility of additional functionalization and expression in the bacterial system, which ensures low production costs.The results of preclinical and clinical studies for diagnosis of malignancies using such proteins as affibody, adnectin, DARPins, etc., have demonstrated their high specificity, affinity, good tolerance and low immunogenicity.

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Amyloid-β Peptide-specific DARPins as a Novel Class of Potential Therapeutics for Alzheimer Disease

Cited by 19 publications

References 45 publications

Ankyrins in human health and disease – an update of recent experimental findings

Ankyrins in human health and disease – an update of recent experimental findings

Effects and mechanism of lipoic acid on beta-amyloid-intoxicated C6 glioma cells

Alternative scaffolds in radionuclide diagnosis of malignancies

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