Serpin-dependent mechanism of protease inhibition. (A) Natively folded serpins present a reactive center loop (RCL) which acts as a bait for interaction with active serine proteases. Upon association, initiation of proteolytic activity by the protease triggers the formation of a Michaelis complex and covalent bonding of the serpin with the protease. (B) The primary outcome of Michaelis complex formation is reconfiguration of the serpin, with the RCL inserting as the third of five strands in the core beta sheet and permanent denaturation of the target serine protease. (C) The secondary and less frequent outcome is completion of proteolytic activity and dissociation of the active serine protease, while the RCL continues to insert as the third of five strands in the serpin core beta sheet.

Serpin-dependent mechanism of protease inhibition. (A) Natively folded serpins present a reactive center loop (RCL) which acts as a bait for interaction with active serine proteases. Upon association, initiation of proteolytic activity by the protease triggers the formation of a Michaelis complex and covalent bonding of the serpin with the protease. (B) The primary outcome of Michaelis complex formation is reconfiguration of the serpin, with the RCL inserting as the third of five strands in the core beta sheet and permanent denaturation of the target serine protease. (C) The secondary and less frequent outcome is completion of proteolytic activity and dissociation of the active serine protease, while the RCL continues to insert as the third of five strands in the serpin core beta sheet.

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... The fibrinolysis starts with converting plasminogen to its active form plasmin which solubilizes the blood clot [7]. Dysregulation of these proteases involved in the coagulation pathway leads to blood-related disorders, chronic lung disease and neurodegenerative diseases [5]. The aetiology of vascular disorders such as atherosclerosis, thrombosis, and aneurysms are also linked to protease activity [8]. ...
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... In addition to its Food and Drug Administrationapproved use for the management of HAE, C1-INH has been investigated to various degrees of therapeutic efficacy in bacterial sepsis, ischemia-reperfusion, and ongoing studies involving transplant applications for C1-INH, including hyperacute rejection and improving organ viability in transport (33,9093). Furthermore, there has long been interest in the therapeutic design of SERPINs with enhanced specificity for applications in an array of diseases where plasma proteases are implicated (32,94,95). Development of this field has primarily leveraged the archetype of SERPIN activity/function, A1AT, which has favorable drug-like properties such as ease of production, bioavailability, and, importantly, its approval for clinical use in the treatment of A1AT deficiency (53,94,96). ...
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... Serine protease inhibitors (serpins) are a superfamily of highly conserved proteins that participate in a number of fundamental physiological processes, such as blood coagulation [5,6], fibrinolysis [7], inflammation [7], signaling cascades [8,9], immune responses [10,11], tumor suppression and hormone carriage [12]. In pathogens, serpins are believed to have specifically evolved to limit or modulate their host immune responses [13]. ...
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... Numerous important physiological processes rely on trypsin-like serine proteases. This includes hemostasis, the immune response system and extracellular matrix remodeling [5][6][7][8]. Dysregulation of these enzymes can lead to severe pathological incidents, which range from cardiovascular disorders to cancer progression or neurodegenerative and inflammation processes [8][9][10]. Moreover, proteases often are virulence factors in infectious diseases. ...
... This includes hemostasis, the immune response system and extracellular matrix remodeling [5][6][7][8]. Dysregulation of these enzymes can lead to severe pathological incidents, which range from cardiovascular disorders to cancer progression or neurodegenerative and inflammation processes [8][9][10]. Moreover, proteases often are virulence factors in infectious diseases. ...
... Computed physicochemical properties, absorption spectra and stability studies are depicted in Supplementary Figures S4 and S5 and Table S1. [8] 2847 ± 844 [47] 14e ...
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... The brinolysis starts with the conversion of plasminogen to its active form plasmin which solubilizes the blood clot [7]. Dysregulation of these proteases involved in coagulation pathway leads to blood related disorders, chronic lung disease and neurodegenerative diseases [5]. The aetiology of vascular disorders such as atherosclerosis, thrombosis, and aneurysms are also linked to protease activity [8]. ...
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