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The Renin-Angiotensin System
Published in Austin E. Doyle, Frederick A. O. Mendelsohn, Trefor O. Morgan, Pharmacological and Therapeutic Aspects of Hypertension, 2020
The development of an orally active converting enzyme inhibitor is an exciting advance. The design of these blockers represent a triumph of molecular pharmacology. They were developed by a consideration of the analogy between converting enzyme, which is, as yet, poorly understood at the molecular level, and carboxypeptidase A, whose active site is better characterized.
Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Enzyme inhibitor drugs are used to treat chronic diseases and disorders such as cardiovascular diseases (angina and myocardial infarction, heart failure, hypertensive heart and rheumatic heart disease, etc.), gastrointestinal diseases, Diabetes Type 2, pain, fever, inflammation, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, asthma and COPD, psoriasis and psoriatic arthritis, different infectious diseases (trypanosomiasis, leishmaniasis, tuberculosis, malaria, acquired immunodeficiency syndrome, etc.), a variety of different types of cancers (see below), some of the rare lysosomal storage diseases, life style related conditions (erectile dysfunction, benign prostatic hyperplasia, alopecia) and many others.
Granulocyte Protease Action: a Possible Cause of Bleeding in Leukemia
Published in László Muszbek, Hemostasis and Cancer, 2019
In principle, the formation of enzyme-inhibitor complex results in the abolishing of enzyme activity. However, this is not a general rule for all protease inhibitors. α2-Macroglobulin-bound proteases, e.g., thrombin, are still capable of cleaving small molecular weight substrates.34 Following the reaction of granulocyte elastase and α2-macroglobulin, the enzyme displays a decreased activity. α2-Macroglobulin-bound elastase can cleave elastin, indicating that a certain enzyme activity is still preserved even for high molecular weight protein substrates.33
Models of enzyme inhibition and apparent dissociation constants from kinetic analysis to study the differential inhibition of aldose reductase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Francesco Balestri, Mario Cappiello, Roberta Moschini, Umberto Mura, Antonella Del-Corso
A variety of graphical approaches have been proposed to disclose and characterise incomplete inhibition16–24. In this study, the rate equations derived from the classical approach16,17, considering the inhibitor targeting the free enzyme or the enzyme-substrate complex were used to fit experimental rate measurements through non-linear regression analysis. In this regard, the trend of the appKM/appkcat versus the inhibitor concentration is proposed as a useful tool to easily disclose the occurrence of an incomplete inhibition. Moreover, the analysis of both complete and incomplete inhibition was here performed also through a non-classical approach, in which it is the substrate that interacts with either the free enzyme or the enzyme-inhibitor complex.
TiO2 nanotube immobilised 5-lipoxygenase-mediated screening and isolation of anti-inflammatory active compounds from the leaves of lonicera japonica thunb
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jinhua Zhu, Danyang Zhou, Dandan Wu, Wei Liu, Xiuhua Liu
Inflammation is a complex physiological response of the body to allergy, trauma, infection, physical and chemical factors and other stimuli. It plays an important role in the pathogenesis of many human diseases, such as cancer, mental disorders, cardiovascular disease, metabolic syndrome, inflammatory bowel disease, arthritis, etc.1–3. The arachidonic acid (AA) metabolic pathway is the main pathway of inflammation development, and 5-lipoxygenase (5-LOX) is a key enzyme in the process of inflammatory response and it is also an important target for the research of anti-inflammatory drugs4,5. Enzyme inhibitor can effectively reduce the catalytic activity of the enzyme and the production of inflammatory mediators, so as to achieve the purpose of reducing inflammation or even blocking the inflammatory response. In the pathogenesis of inflammation, the over-expression of cytokines produced by macrophages can induce the occurrence of acute and chronic inflammatory diseases6. NO is an important inflammatory mediator and is involved in the regulation of many biological activities7,8. Under normal conditions, NO mainly plays a role in regulation and balance, and the over-expression of NO can stimulate superoxide anion free radicals to form peroxynitrite, thereby causing oxidative stress and promoting the occurrence and development of inflammation9. Therefore, NO is regarded as one of the important factors to judge the inflammatory response10.
Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance
Published in Drug Delivery, 2022
Muhammad Umair Amin, Sajid Ali, Muhammad Yasir Ali, Dominik C. Fuhrmann, Imran Tariq, Benjamin S. Seitz, Eduard Preis, Jana Brüßler, Bernhard Brüne, Udo Bakowsky
In this study, we have developed a combined drug delivery system to encounter the hypoxia-related resistance of cancer cells to weakly basic anticancer drugs. The co-delivery of the CA-IX inhibitor and Dox was successfully attained by coating carbonic anhydrase inhibitor-loaded liposomes to Dox-loaded MSNPs. In vitro cytotoxic experiments were performed under normoxia and hypoxia, and it was shown that the CA-IX enzyme was overexpressed under hypoxic conditions. The enzyme inhibitor can be effective only when the enzyme is overexpressed in hypoxia. Furthermore, the improved inhibitory effects of the CA-IX inhibitor were observed when loaded in liposomes compared to pure enzyme inhibitors, indicating higher cellular uptake because of liposomal biocompatibility. Lesser cytotoxic effects of Dox under hypoxia in the absence of the CA-IX inhibitor are due to acidification of the extracellular environment, resulting in ionization of Dox and ultimately lesser uptake. However, the combined effects of enzyme inhibitor and Dox have synergistic cytotoxic effects under hypoxia because of CA-IX enzyme inhibition.