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Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
The chief characteristic of cystatins, as implied by their name, is the ability to inhibit cysteine proteinases. Cystatins do not inhibit proteinases with other catalytic mechanisms, and they are usually thought to be selective for cysteine proteinases of the papain superfamily, which include the lysosomal proteinases cathepsin B, H, and L, and the cytosolic calpains. Some evidence suggests that other types of cysteine proteinases, including clostripain and polioviral proteinases, may be inhibited, although the interactions have not been studied in detail. Members of this superfamily are unique among the inhibitors considered in this chapter, since some of the members of families 1 and 2 are able to inhibit the exopeptidase known as dipeptidyl peptidase I, an enzyme that sequentially removes dipeptides from the N terminus of proteins.
The role of precision medicine in bronchiectasis: emerging data and clinical implications
Published in Expert Review of Respiratory Medicine, 2023
Grace Oscullo, David de la Rosa, Marta Garcia Clemente, Rosa Giron, Rafael Golpe, Luis Máiz, Miguel Angel Martinez-Garcia
The inhibition of neutrophilic elastase (NE) is the treatment that has been most fully evaluated. This involves either blocking NE’s peripheral action to prevent the activation of serine proteases in the bone marrow or reducing the number of neutrophils entering tissues by preventing chemotaxis. In the former case, preliminary studies have been published with the oral NE inhibitors AZD966843 [127] and BAY85–850144 [128], but their results were inconclusive, due to the studies’ short duration. A trial with the inhaled drug CHF 6333 is currently in progress [129]. The evidence from the second approach is more substantial, especially with respect to Brensocatib, an oral inhibitor of dipeptidyl peptidase 1 (or cathepsin C). One 24-week trial has already shown a reduction in exacerbations [93], but new and longer studies are already underway with this and other similar drugs. Finally, we must highlight a preliminary study with the oral CXCR2 antagonist AZD5069 [130], as its results have motivated the launch of new trials with this molecule in COPD [131].
Classes of drugs that target the cellular components of inflammation under clinical development for COPD
Published in Expert Review of Clinical Pharmacology, 2021
Maria Gabriella Matera, Luigino Calzetta, Rosa Annibale, Francesco Russo, Mario Cazzola
Neutrophils are characterized by the presence of specialized granules that include a number of antimicrobial peptides, myeloperoxidase (MPO), the serine proteases proteinase 3 (PR3), cathepsin G, neutrophil elastase (NE), the enzymatic inactive protease cationic antimicrobial protein of 37 kd (CAP37, aka azurocidin) and the neutrophil serine protease 4 (NSP4), cysteine proteases, lactoferrin, lipocalin, metalloproteinases (MMPs) and gelatinase [8]. They are named azurophil granule proteins and are initially synthesized as inactive zymogens and are converted into their mature active form by cathepsin C, also known as dipeptidyl peptidase 1 (DPP1) [9]. Under normal conditions, a large fraction of neutrophils are tethered to the lining of the lung vasculature. They infiltrate the lungs to strategically coordinate physiological surveillance responses [10] and regulate the numbers of alveolar macrophages [11]. Specific receptors of human neutrophils are classically C-X-C Chemokine Receptor (CXCR)1 and CXCR2 but also C- C Chemokine Receptor (CCR)1, CCR2, CCR3, CCR5, CXCR3, and CXCR4 [12], although expression of CCRs are absent under normal conditions [13] but during an inflammatory disease neutrophils expand their CR expression repertoire [14]. Exogenous and endogenous inflammatory stimuli through CRs can trigger recruitment and activation of circulating neutrophils [15]. The activated neutrophils degranulate and release several cytotoxic products, including ROS, granular enzymes, and various pro-inflammatory cytokines [12]. An abundant release of neutrophil granular enzymes in the alveolar compartment as well as the airways can trigger collateral pulmonary tissue damage and also perpetuate lung inflammation [1,12]. Activated neutrophils also extrude neutrophil extracellular traps (NETs), which are acellular structures consisting of fibers of chromatin decorated with antimicrobial neutrophil granular proteins, such as MPO and NE and can simultaneously trap and kill various extracellular pathogens by providing a highly concentrated supply of antimicrobial compounds. NETs are augmented in COPD and a dysregulated induction of their formation may cause localized NET burden and contribute to NETopathic lung inflammation [16].