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Intracellular Peptide Turnover: Properties and Physiological Significance of the Major Peptide Hydrolases of Brain Cytosol
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
The oligopeptidase nature of the enzyme was revealed by the resistance of the 22 amino acid enkephalin-containing peptide BAM 22P to hydrolysis. When dynorphin 1–8 was administered i.c.v. to rats and CSF was collected from the cisterna magna, the peptide was barely detectable. However when a specific soluble metalloendopeptidase inhibitor (see below) was co-administered, a large increase in the recovery of this peptide was obtained90. Similarly co-administration of a soluble metalloendopeptidase inhibitor with either dynorphin 1–8 or Met-enkephalin-Arg6-Gly7-Leu8 increased the antinociception above that seen with peptide by itself91, and central administration of a specific inhibitor increased antinociception following intermittent cold water swims in rats92.
Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Itzhel García-Torres, Ignacio De la Mora-De la Mora, Gabriel López-Velázquez, Nallely Cabrera, Luis Antonio Flores-López, Ingeborg Becker, Juliana Herrera-López, Roberto Hernández, Ruy Pérez-Montfort, Sergio Enríquez-Flores
Studies focussed on drug discovery for the treatment of CD follow two main lines of research: phenotypic screening of compound libraries and target-based drug discovery14. High throughput screening assays have been conducted on thousands of natural and synthetic compounds, and a few have advanced to clinical trials listed in the Clinical Trials database (https://clinicaltrials.gov)15. Some therapeutic targets studied include sterol-14-α demethylase (CYP51)16, the 80 kDa enzyme prolyl oligopeptidase (Tc80)17, cysteine peptidase cruzipain18,19, the proteasome20, trypanothione reductase21, superoxide dismutase (Fe-SOD) and triosephosphate isomerase (TIM)22. TIM catalyses the interconversion of DHAP and GAP, which is a vital mechanism for the complete catabolism of glucose and the generation of net energy in the form of ATP and metabolites such as NADH. TIM is located in the glycosome, which is a distinctive organelle from kinetoplastid protozoans such as Leishmania spp, T. brucei, and T. cruzi23. Glycosomes are essential for parasite survival in the bloodstream since glycolysis is the only source of ATP at this stage24.
Unraveiling the correlation among neurodevelopmental and inflammatory biomarkers in patients with chronic schizophrenia
Published in Nordic Journal of Psychiatry, 2022
João V. Nani, Priscila G. C Almeida, Cristiano Noto, Rodrigo A. Bressan, Elisa Brietzke, Mirian A. F Hayashi
Nuclear distribution element like-1 (Ndel1) oligopeptidase is a cytosolic enzyme that cleaves small neuropeptides which were suggested to play several roles, including as endogenous antipsychotic and/or in neurogenesis/neuromodulation/neuroprotection [1,2]. Ndel1 also forms complexes with cytosolic cytoskeleton proteins, which are required for neurite outgrowth, neuronal migration and neurogenesis, suggesting its potential role in the susceptibility to develop psychiatric disorders, supporting the neurodevelopmental hypothesis of schizophrenia (SCZ) [3]. A significant lower Ndel1 activity was observed in antipsychotic-naïve first-episode psychosis (FEP) subjects compared with healthy controls (HCs), suggesting Ndel1 oligopeptidase activity as a potential biomarker of early stages and/or disease progression of SCZ [4]. Moreover, a linear correlation between decreases in Ndel1 activity and symptom amelioration following the treatment with risperidone was recently demonstrated by us in FEP individuals [4]. In line with this, chronic SCZ patients also show lower Ndel1 activity compared with HCs [5], as well as long-term treatment with typical or atypical antipsychotics decreased the Ndel1 activity in blood and brain of an animal model for SCZ studies [6]. We have also demonstrated a reduced Ndel1 activity in blood and brain of a transgenic animal model for SCZ studies, which presents abnormal dopaminergic signaling and disrupted neurodevelopment [2].
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
Many more ubiquitous peptidases like plasmin and furin circulate in blood. Thimet oligopeptidase (EC 3.4.24.15) is a metalloprotease associated with peptide processing in nervous system structures. It degrades several peptides, including bradykinin, amyloid beta, and the major histocompatibility complex class I molecules [77]. Nardilysin (3.4.24.61) is a metalloendopeptidase and promotes ectodomain shedding of the precursor forms of various growth factors and cytokines [78]. Neprilysin (neutral endopeptidase, NEP, EC 3.4.24.11) is a membrane-bound zinc-metallopeptidase enzyme and cleaves various peptides, including natriuretic and bombesin-like peptides, endothelin-1, and substance P [79]. Numerous peptidases are expressed in various tissues and secreted into plasma. Whether the peptidases are concerns for peptide, protein, and antibody drugs depends on the peptidase concentration in the blood.