China
Africa
Explore chapters and articles related to this topic
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.
A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications
Published in Expert Opinion on Therapeutic Patents, 2019
L Crocetti, MT Quinn, IA Schepetkin, MP Giovannoni
Several key advances in the last couple of years will likely stimulate further development of newer HNE inhibitors. The first originates from the observation that in addition to HNE, other proteases contribute to tissue damage; thus, dual HNE/PR3 inhibitors have been proposed as an innovative approach for the treatment of neutrophilic inflammatory diseases by Hwang and coworkers [174,175], opening a new window in the discovery of new drugs. Second, the activity of neutrophil serine proteases, including elastase and Pr3, has been implicated in some autoimmune diseases, such as type 1 diabetes (T1D) [94]. Although the role of neutrophils in the development of T1D remains unknown, a recent patent [176] reports that the serum concentration and the enzymatic activities of neutrophil elastase and Pr3 are diagnostic biomarkers for the risk of developing autoimmune diabetes. Another interesting approach being considered to regulate levels of protease activity and restore the protease-antiprotease balance is to indirectly modulate HNE function by inhibiting those peptidases that active this enzyme during development in the bone marrow. For example, DPP1 (dipeptidyl peptidase 1 or Cathepsin C) is a lysosomal cysteine protease that plays a key role in the activation of the proinflammatory neutrophil serine proteases, HNE, PR3, and Cathepsin G by cleaving the N-terminal dipeptide during neutrophil maturation. The inhibition of DPP1 could generate neutrophils lacking these active proteases, thereby reducing the local release and the subsequent damage [177].