Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Bai, Ping; Mondal, Prasenjit; Bagdasarian, F Andrew; Rani, Nisha; Liu, Yan; Gomm, Ashley; Tocci, Darcy R.; Choi, Se Hoon; Wey, Hsiao‐Ying; Tanzi, Rudolph E.; Zhang, Can; Wang, Changning

doi:10.1016/j.apsb.2022.05.017

Cited by 23 publications

(22 citation statements)

References 48 publications

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“…Compound B showed three types of interactions with the binding pocket of HDAC6 which are two H-bonds with GLY582 and TYR745 residues; pi–pi interactions through PHE643, PHE583, and HIE614; and hydrophobic interactions with the PHE643, TYR745, PRO571, PHE583, CYS584, PRO464, and LEU712 amino residues ( Figure 4 B and Figure 5 B). HDAC6 binding affinity and van der Waals interactions are enhanced by pointing to the Phe643 and Leu 712 residues in the so-called L1-loop pocket, as studied by Bai [ 47 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

et al. 2023

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Breast cancer (BC) is one of the main types of cancer that endangers women’s lives. The characteristics of triple-negative breast cancer (TNBC) include a high rate of recurrence and the capacity for metastasis; therefore, new therapies are urgently needed to combat TNBC. Dual targeting HDAC6 and Hsp90 has shown good synergistic effects in treating metastatic TNBC. The goal of this study was to find potential HDAC6 and Hsp90 dual inhibitors. Therefore, several in silico approaches have been used. An e-pharmacophore model generation based on the HDAC6-ligand complex and subsequently a pharmacophore-based virtual screening on 270,450 natural compounds from the ZINC were performed, which resulted in 12,663 compounds that corresponded to the obtained pharmacophoric hypothesis. These compounds were docked into HDAC6 and Hsp90. This resulted in the identification of three compounds with good docking scores and favorable free binding energy against the two targets. The top three compounds, namely ZINC000096116556, ZINC000020761262, and ZINC000217668954, were further subjected to ADME prediction and molecular dynamic simulations, which showed promising results in terms of pharmacokinetic properties and stability. As a result, these three compounds can be considered potential HDAC6 and Hsp90 dual inhibitors and are recommended for experimental evaluation.

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Section: Resultsmentioning

confidence: 99%

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

et al. 2023

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“…The standing committee on animals approved the animal protocol of the PET study at Massachusetts General Hospital, Boston, MA (Protocol number: 2020N000042). The general procedure for rodent PET/ computed tomography (CT) imaging studies was described previously 62,63 . Briefly, aged mice (18 months old) were arranged in a carrier under anesthesia with 1% isoflurane (Patterson Veterinary Supply, Inc.) and 2 L/minute medical oxygen for the duration of scanning.…”

Section: Methodsmentioning

confidence: 99%

“…The general procedure for rodent PET/ computed tomography (CT) imaging studies was described previously. 62,63 Briefly, aged mice (18 months old) were arranged in a carrier under anesthesia with 1% isoflurane (Patterson Veterinary Supply, Inc.) and 2 L/minute medical oxygen for the duration of scanning.…”

Section: Pet Study Of Micementioning

confidence: 99%

Blood tau‐PT217 contributes to the anesthesia/surgery‐induced delirium‐like behavior in aged mice

Liang

Bai

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONBlood phosphorylated tau at threonine 217 (tau‐PT217) is a newly established biomarker for Alzheimer's disease and postoperative delirium in patients. However, the mechanisms and consequences of acute changes in blood tau‐PT217 remain largely unknown.METHODSWe investigated the effects of anesthesia/surgery on blood tau‐PT217 in aged mice, and evaluated the associated changes in B cell populations, neuronal excitability in anterior cingulate cortex, and delirium‐like behavior using positron emission tomography imaging, nanoneedle technology, flow cytometry, electrophysiology, and behavioral tests.RESULTSAnesthesia/surgery induced acute increases in blood tau‐PT217 via enhanced generation in the lungs and release from B cells. Tau‐PT217 might cross the blood–brain barrier, increasing neuronal excitability and inducing delirium‐like behavior. B cell transfer and WS635, a mitochondrial function enhancer, mitigated the anesthesia/surgery‐induced changes.DISCUSSIONAcute increases in blood tau‐PT217 may contribute to brain dysfunction and postoperative delirium. Targeting B cells or mitochondrial function may have therapeutic potential for preventing or treating these conditions.

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“…In vitro and in vivo studies have shown the involvement of HDAC6 in the deacetylation of α- and β-tubulin. Upregulation of HDAC6 in mammalian cells induces tubulin hypoacetylation, while its inhibition by pharmacological or genetic interactions causes microtubule hyperacetylation [ 166 – 169 ].…”

Section: Ptms Of Tubulin – Limelight On Acetylationmentioning

confidence: 99%

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Naren

Samim

Tryphena

et al. 2023

Transl Neurodegener

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The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse. Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, respectively. Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs. Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan. The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease (PD). PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels. Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD. The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored. Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it. Graphical abstract

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Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Cited by 23 publications

References 48 publications

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

Blood tau‐PT217 contributes to the anesthesia/surgery‐induced delirium‐like behavior in aged mice

Microtubule acetylation dyshomeostasis in Parkinson’s disease

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