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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
Recently cloned enzymes have sequence homology to thimet oligopeptidase. A mitochondrial intermediate peptidase which removes an N-terminal octapeptide from a mitochondrial precursor protein has 44% similarity to thimet oligopeptidase113. Similarly an enzyme purified from rabbit liver microsomes with a specificity for peptides containing Arg in the P1 and P4 positions has 60% sequence homology to thimet oligopeptidase114. The latter enzyme is proposed to play a role in prohormone processing. This microsomal processing enzyme is also 91% homologous to angiotensin II binding protein105. Thimet oligopeptidase has 24% amino acid identity to a 565 residue overlap with the metalloproteinase encoding gene opdA from Salmonella typhimurium115. Therefore thimet oligopeptidase is part of a newly recognized family of metalloproteinases.
Exosomes: from biology to immunotherapy in infectious diseases
Published in Infectious Diseases, 2023
Velia Verónica Rangel-Ramírez, Hilda Minerva González-Sánchez, César Lucio-García
Exosomes are now intensively studied as possible biomarkers in diagnosis, disease progression, prognosis and therapy monitoring during infectious diseases [23,75,78,409,410]. The cargo composition of exosomes derived from healthy controls and individuals undergoing an infection has been proven to be different, and in some instances track with pathology or disease progression (as reviewed in [36,409]). For instance, exosomal protein CD81 was found elevated in the serum of hepatitis C patients when compared to healthy controls [24], and the thimet oligopeptidase A could be a potential diagnostic marker for T. brucei [411]; additionally, urinary exosomes can help to detect kidney diseases during viral and bacterial infections [75,76,412]. Moreover, studies with oncogenic viruses suggest that cancer-secreted exosomes can change the tumor microenvironment enhancing metastasis, inflammation, and angiogenesis [101,172].
Small molecule neurolysin activators, potential multi-mechanism agents for ischemic stroke therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Shiva Hadi Esfahani, Thomas J. Abbruscato, Paul C. Trippier, Vardan T. Karamyan
Based on the hypothesized cerebroprotective function of Nln in the post-stroke brain, a substantial effort has been made in the last several years to identify and develop small, ‘drug-like’ molecules that can selectively enhance the catalytic activity of the peptidase. For this, the structure of Nln was explored by a computational approach to select a druggable surface pocket, followed by molecular docking and in silico screening of ~140,000 compounds, and identification of two dipeptides, L-histidyl-L-histidine and L-histidyl-L-tyrosine as potential Nln activators [10]. Further detailed in vitro pharmacological studies determined that these dipeptides increase Nln-mediated hydrolysis of a synthetic fluorescence substrate as well as endogenous substrates BK, NT, and angiotensin I in a concentration-dependent manner. Notably, the identified dipeptides enhanced the rate of synthetic substrate hydrolysis by both recombinant (human and rat) and mouse brain-purified Nln (micromolar A50 and ≥ 300% Amax), while minimally affecting activity of closely related enzymes thimet oligopeptidase, neprilysin, angiotensin-converting enzyme (ACE), and ACE2 [10]. This was the first study documenting that the activity of Nln can be enhanced by small molecules and offered a chemical scaffold for development of high-potency, ‘drug-like’ Nln activators. Importantly, the binding site of Nln activators and the mechanism(s) leading to enhanced catalytic activity of this peptidase are poorly understood and are a subject of our ongoing studies.
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.