A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer’s Disease

Abstract

Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra-or extracellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-Aβ 1-42 mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1β to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic Caenorhabditis elegans (C. elegans) strains that express human Aβ 1-42 in muscle or neurons, PNR502 rescued Aβ-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively. Moreover, in C. elegans with neuronal expression of Aβ 1-42 , a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (P < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (P ≤ 0.001). Given that PNR502 can slow, prevent, or reverse Alzheimer-like protein aggregation in human-cell-culture and animal models, and that its principal predicted and observed binding targets are proteins previously implicated in Alzheimer's, we propose that PNR502 has therapeutic potential to inhibit cerebral Aβ 1-42 aggregation and prevent or reverse neurodegeneration.

Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

“…The structures of SARS-CoV-2 proteins used in this study were retrieved from I-TASSER (neural networkbased structure predictions) [9]. Proteins were preprocessed using the Protein Preparation Wizard module of Schrödinger's Prime module by the MMGBSA method, using molecular mechanics, the generalized Born solvent model, and solvent accessibility [18][19][20].…”

Label-free photothermal disruption of cytotoxic aggregates rescues pathology in a C. elegans model of Huntington’s disease

“…Many cell and whole-animal models of neuropathic aggregation have been developed, including C. elegans models of amyloidopathy elicited by expression of human “seed” proteins Aβ 1–42 , tau, TDP-43, α-synuclein, and polyglutamine tracts fused to yellow fluorescent protein 3 , 7 , 10 , 37 – 42 . We selected AM141, a disease-threshold model of polyglutamine tract expansion, because it displays age-progressive accrual of relatively large aggregates without transgene induction, resulting in functional motility impairment, reduced lifespan, and drug-induced diminution of aggregates 7 , 41 , 42 .…”

Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

“…The system was next equilibrated using the NPT protocol (constant number of particles, pressure and temperature) with default temperature (300 o K) and pressure (1 bar). MD simulations were then conducted for 100-200 ns using Desmond's GPU-based simulation method [18][19][20][21][22]. Results were analyzed using the Simulation Interactions Diagram module from Schrödinger Maestro.…”

“…The top 15 drug candidates were then selected for next-level screening. (2) The Gibbs Free Energy of binding (ΔGbinding) was calculated withinSchrödinger's Prime module by the MMGBSA method, using molecular mechanics, the generalized Born solvent model, and solvent accessibility[18][19][20].…”