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INHIBITOR

AMYLOID INHIBITORS

Molecular agents that specifically bind and neutralize misfolded and toxic amyloids may find application in attenuating progression of neuronal diseases. However, high structural similarities between the wild-type and mutant amyloid limit the utility of this approach. We are addressing this challenge by converting promiscuous proteins into highly specific aggregation inhibitors of SOD1, Aβ42 and Tau. We utilize computational algorithms for mapping protein surfaces predisposed to inhibitor intermolecular interactions to construct a focused protein inhibitor library, complemented with an experimental platform based on yeast surface display for affinity and specificity screening.

AB

On and off Aβ aggregation pathways in solution and in membranes. In the presence of membranes (ii), endogenous Aβ forms a large portion of on-pathway molecules with an α-helical structure in the early aggregation stages, followed by the formation of mature anti-parallel β-sheet fibrils, which exhibit higher toxicity than the parallel β-sheet Aβ fibrils formed in aqueous solution (i). Binding to membrane components (e.g., GM1) allows the anti-parallel β-sheet Aβ fibrils to bind to molecules, such as toll-like receptors (TLRs), and thereby to initiate cell death by apoptosis. Similarly, in the presence of DOPC and DOPG, Aβ forms globular aggregates that are toxic to cells. Red circles indicate the toxic species in each pathway; large arrows indicate accelerated formation of the species.

Related publications

APPI-Derived Cyclic Peptide Enhances Aβ42 Aggregation and Reduces Aβ42-Mediated Membrane Destabilization and Cytotoxicity

Lacham-Hartman S, Moshe R, Ben-Zichri S, Shmidov Y, Bitton R, Jelinek R, Papo N. ACS Chem Neurosci. 2023

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Synergistic Activity of Anticancer Polyphenols Embedded in Amphiphilic Dendrimer Nanoparticles

Ben-Zichri S, Meltzer M, Lacham-Hartman S, Kolusheva S, Hadad U, Papo N, and Jelinek R. ACS Appl. Polym. Mater. 2022

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Bcl-2-Homology-Only Proapoptotic Peptides Modulate β-Amyloid Aggregation and Toxicity

Ben-Zichri S, Malishe R, Oren O, Bloch DN, Taube R, Papo N, Jelinek R. ACS Chem. Neurosci. 2021

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Amyloid β structural polymorphism, associated toxicity and therapeutic strategies

Oren O, Taube R, Papo N,  Cell Mol Life Sci​.  2021

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A Mechanism for the Inhibition of Tau Neurotoxicity: Studies with Artificial Membranes, Isolated Mitochondria, and Intact Cells.

Naveh Tassa S, Ben Zichri S, Lacham-Hartman S, Oren O, Slobodnik Z, Eremenko E, Toiber D, Jelinek R, Papo N. ACS Chem Neurosci. 2021.

 

The pro-apoptotic domain of BIM protein forms toxic amyloid fibrils.

Malishev R, Ben-Zichri S, Oren O, Shauloff N, Peretz T, Taube R, Papo N, Jelinek R.Cell Mol Life Sci. 2021.

 

Aβ42 Double Mutant Inhibits Aβ42-Induced Plasma and Mitochondrial Membrane Disruption in Artificial Membranes, Isolated Organs, and Intact Cells.

Oren O, Ben Zichri S, Taube R, Jelinek R, Papo N. ACS Chem Neurosci. 2020.

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A hyperthermophilic protein G variant engineered via directed evolution prevents the formation of toxic SOD1 oligomers.

Dagan B, Oren O, Banerjee V, Taube R, Papo N. Proteins. 2019.

 

An Engineered Variant of the B1 Domain of Protein G Suppresses the Aggregation and Toxicity of Intra- and Extracellular Aβ42.

Banerjee V, Oren O, Dagan B, Taube R, Engel S, Papo N. ACS Chem Neurosci. 2019. 

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An Aβ42 variant that inhibits intra- and extracellular amyloid aggregation and enhances cell viability.

Oren O, Banerjee V, Taube R, Papo N. Biochem J. 2018.

 

MIF inhibits the formation and toxicity of misfolded SOD1 amyloid aggregates: implications for familial ALS.

Shvil N, Banerjee V, Zoltsman G, Shani T, Kahn J, Abu-Hamad S, Papo N, Engel S, Bernhagen J, Israelson A. Cell Death Dis. 2018.

 

A computational combinatorial approach identifies a protein inhibitor of superoxide dismutase 1 misfolding, aggregation, and cytotoxicity.

Banerjee V, Oren O, Ben-Zeev E, Taube R, Engel S, Papo N. J Biol Chem. 2017.

 

Superoxide Dismutase 1 (SOD1)-Derived Peptide Inhibits Amyloid Aggregation of Familial Amyotrophic Lateral Sclerosis SOD1 Mutants.

Banerjee V, Shani T, Katzman B, Vyazmensky M, Papo N, Israelson A, Engel S. ACS Chem Neurosci. 2016.

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