The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

Gautieri, Alfonso; Beeg, Marten; Gobbi, Marco; Rigoldi, Federica; Colombo, Laura; Salmona, Mario

doi:10.3390/ijms20184641

Cited by 36 publications

(28 citation statements)

References 45 publications

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“…Also, the hydrophobic nature of the cyclic rings in CMT-3 would serve to target the hydrophobic core of the fibril. The binding mode is similar to the one recently proposed for the binding of DOX to Aβ amyloid fibers 63 . In this way, the binding mode seems to be dependent on the conformation of the aggregation-prone segment rather than on its sequence, and would explain the capability of tetracyclines to inhibit the amyloid aggregation of diverse proteins such as Aβ 64 , PrP 65 , α-synuclein 17 , 66 or β2-microglobulin 67 .…”

Section: Discussionsupporting

confidence: 83%

CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects

González‐Lizárraga

Ploper

Ávila

et al. 2020

Sci Rep

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Parkinson's disease (PD) is a neurodegenerative disorder for which only symptomatic treatments are available. Repurposing drugs that target α-synuclein aggregation, considered one of the main drivers of PD progression, could accelerate the development of disease-modifying therapies. In this work, we focused on chemically modified tetracycline 3 (CMT-3), a derivative with reduced antibiotic activity that crosses the blood–brain barrier and is pharmacologically safe. We found that CMT-3 inhibited α-synuclein amyloid aggregation and led to the formation of non-toxic molecular species, unlike minocycline. Furthermore, CMT-3 disassembled preformed α-synuclein amyloid fibrils into smaller fragments that were unable to seed in subsequent aggregation reactions. Most interestingly, disaggregated species were non-toxic and less inflammogenic on brain microglial cells. Finally, we modelled the interactions between CMT-3 and α-synuclein aggregates by molecular simulations. In this way, we propose a mechanism for fibril disassembly. Our results place CMT-3 as a potential disease modifier for PD and possibly other synucleinopathies.

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Section: Discussionsupporting

confidence: 83%

CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects

González‐Lizárraga

Ploper

Ávila

et al. 2020

Sci Rep

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“…Tetracycline binds preferably to polar or slightly lipophilic RBD residues, which as observed in the experiment comprise the majority of amino acids that form persistent hydrogen bonds with ACE2 7,8,12,12,13 . Other tetracycline derivatives such as doxycycline or minocycline are known to be more lipophilic 3,6,13 and may therefore prefer nonpolar residues 14 that are often buried beneath the solvent accessible surface area of the spike protein. Indeed, the RBD residues that have the highest binding affinity to doxycycline are Tyr 449, Gly 447, Val 445, Gly 496, of which only two are RBD amino acids that engage in persistent hydrogen bonding with ACE2.…”

Section: Resultsmentioning

confidence: 72%

Tetracycline as an inhibitor to the SARS‐CoV‐2

Zhao

Patankar

2021

J of Cellular Biochemistry

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The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains an extant threat against public health on a global scale. Cell infection begins when the spike protein of SARS‐CoV‐2 binds with the human cell receptor, angiotensin‐converting enzyme 2 (ACE2). Here, we address the role of tetracycline as an inhibitor for the receptor‐binding domain (RBD) of the spike protein. Targeted molecular investigation show that tetracycline binds more favorably to the RBD (−9.40 kcal/mol) compared to doxycycline (−8.08 kcal/mol), chloroquine (−6.31 kcal/mol), or gentamicin (−4.83 kcal/mol) while inhibiting attachment to ACE2 to a greater degree (binding efficiency of 2.98 kcal/(mol nm 2 ) for tetracycline–RBD, 5.16 kcal/(mol nm 2 ) for doxycycline–RBD, 5.59 kcal/(mol nm 2 ) for chloroquine–RBD, and 7.02 kcal/(mol nm 2 ) for gentamicin–RBD. Stronger inhibition by tetracycline is verified with nonequilibrium PMF calculations, for which the tetracycline–RBD complex exhibits the lowest free energy profile along the dissociation pathway from ACE2. Tetracycline binds to tyrosine and glycine residues on the viral contact interface that are known to modulate molecular recognition and bonding affinity. These RBD residues also engage in significant hydrogen bonding with the human receptor ACE2. The ability to preclude cell infection complements the anti‐inflammatory and cytokine suppressing capability of tetracycline; this may reduce the duration of ICU stays and mechanical ventilation induced by the coronavirus SARS‐CoV‐2.

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“…36 Gunnar F. Schröder and coworkers reported one Aβ42 fibrils structure (PDB ID: 5OQV) obtained by cryo-electron microscopy in 2017, and the structure had been widely used as a molecular docking model to study ligands and Aβ42 fibrils interactions ever since. [37][38][39] The protein structures for Aβ42 oligomers are rare due to their heterogeneous and aggregation-prone nature.…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Amphiphilic Stilbene Derivatives Attenuate the Neurotoxicity of Soluble Aβ42 Oligomers by Controlling Their Interactions with Cell Membranes

Yu¹,

Guo²,

Cho³

et al. 2021

Preprint

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Misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer’s disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-β (Aβ) plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro binding experiments (i.e., fluorescence saturation assays) demonstrated that these amphiphilic compounds show high binding affinity to both Aβ plaques and oligomers, and six of them exhibit even higher binding affinity toward Aβ oligomers. These amphiphilic compounds can also <a>label ex vivo Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. </a>Molecular docking studies were performed to help understand the structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate Cu2+-Aβ induced toxicity in mouse neuroblastoma N2a via cell toxicity assays. In addition, <a>confocal</a> fluorescence imaging studies provided evidence that compounds ZY-15-MT and ZY-15-OMe can disrupt <a>the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell</a> membranes. Overall, these studies suggest that developing compounds with amphiphilic properties that target Aβ oligomers can be an effective strategy for small molecule AD therapeutics.

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The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

Cited by 36 publications

References 45 publications

CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects

CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects

Tetracycline as an inhibitor to the SARS‐CoV‐2

Amphiphilic Stilbene Derivatives Attenuate the Neurotoxicity of Soluble Aβ42 Oligomers by Controlling Their Interactions with Cell Membranes

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