Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein

Šunderić, Miloš; Vasovic, Tamara; Milčić, Miloš K.; Miljević, Čedo; Nedić, Olgica; Nikolić, Milan; Gligorijević, Nevenka

doi:10.1016/j.ijbiomac.2021.04.155

Cited by 5 publications

(2 citation statements)

References 51 publications

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“…It is possible that the expression of genes encoding other enzymes capable of modulating protein synthesis was post-transcriptionally affected by clozapine. While more evidence is necessary to assess such a possibility, clozapine was associated with the oxidation of protein products [43] and interacted with an anti-proteinase [44] responsible for the modulation of protein degradation. Taken together, clozapine may affect the activity and susceptibility to proteolyse proteins [45] and, indirectly, the total amount of protein products detected.…”

Section: Discussionmentioning

confidence: 99%

Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis

Liu

Truong

Bortolasci

et al. 2022

IJMS

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Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis

Liu

Truong

Bortolasci

et al. 2022

IJMS

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“…The biggest increase in the oxidative stability of HHb in the complex with clozapine is not surprising. Its antioxidant properties are well known in various in vitro models [40], and it has shown similar protective effects on plasma proteins fibrinogen [41] and alpha-2-macroglobulin [42]. The suggested therapeutic plasma clozapine concentration (300 to 700 ng/mL) [43] is substantially higher than ziprasidone and sertindole.…”

Section: Effect Of Atypical Antipsychotics On Oxidant-assisted Human ...mentioning

confidence: 99%

Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?

Arizanović

Gligorijević

Cvijetić

et al. 2023

IJMS

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Packed with hemoglobin, an essential protein for oxygen transport, human erythrocytes are a suitable model system for testing the pleiotropic effects of lipophilic drugs. Our study investigated the interaction between antipsychotic drugs clozapine, ziprasidone, sertindole, and human hemoglobin under simulated physiological conditions. Analysis of protein fluorescence quenching at different temperatures and data obtained from the van’t Hoff diagram and molecular docking indicate that the interactions are static and that the tetrameric human hemoglobin has one binding site for all drugs in the central cavity near αβ interfaces and is dominantly mediated through hydrophobic forces. The association constants were lower-moderate strength (~104 M−1), the highest observed for clozapine (2.2 × 104 M−1 at 25 °C). The clozapine binding showed “friendly” effects: increased α-helical content, a higher melting point, and protein protection from free radical-mediated oxidation. On the other hand, bound ziprasidone and sertindole had a slightly pro-oxidative effect, increasing ferrihemoglobin content, a possible “foe”. Since the interaction of proteins with drugs plays a vital role in their pharmacokinetic and pharmacodynamic properties, the physiological significance of the obtained findings is briefly discussed.

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Glucocorticoids promote steroid-induced osteonecrosis of the femoral head by down-regulating serum alpha-2-macroglobulin to induce oxidative stress and facilitate SIRT2-mediated BMP2 deacetylation

Fang,

He,

You

et al. 2024

Free Radical Biology and Medicine

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Antipsychotic clozapine binding to alpha-2-macroglobulin protects interacting partners against oxidation and preserves the anti-proteinase activity of the protein

Abstract: Figure S1. Optimized structures of two atropisomers of the clozapine molecule. Left: P (plus) atropisomer. Right: M (minus) atropisomer. Two atropisomers are also enantiomers.

Cited by 5 publications

References 51 publications

Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis

Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis

Human Hemoglobin and Antipsychotics Clozapine, Ziprasidone and Sertindole: Friends or Foes?

Glucocorticoids promote steroid-induced osteonecrosis of the femoral head by down-regulating serum alpha-2-macroglobulin to induce oxidative stress and facilitate SIRT2-mediated BMP2 deacetylation

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