Abstract
Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) superfamily with antiprotease activity, is the main physiological inhibitor of tissue-type (tPA) and urokinase-type (uPA) plasminogen activators (PAs). Apart from being crucially involved in fibrinolysis and wound healing, PAI-1 plays a pivotal role in various acute and chronic pathophysiological processes, including cardiovascular disease, tissue fibrosis, cancer, and age-related diseases. In the prospect of treating the broad range of PAI-1-related pathologies, many efforts have been devoted to developing PAI-1 inhibitors. The use of these inhibitors, including low molecular weight molecules, peptides, antibodies, and antibody fragments, in various animal disease models has provided ample evidence of their beneficial effect in vivo and moved forward some of these inhibitors in clinical trials. However, none of these inhibitors is currently approved for therapeutic use in humans, mainly due to selectivity and toxicity issues. Furthermore, the conformational plasticity of PAI-1, which is unique among serpins, poses a real challenge in the identification and development of PAI-1 inhibitors. This review will provide an overview of the structural insights into PAI-1 functionality and modulation thereof and will highlight diverse approaches to inhibit PAI-1 activity.
Highlights
Hemostasis is an essential physiological process that preserves the integrity of the vascular system and secures sufficient blood flow throughout the circulatory system
Structural and site-directed mutagenesis results have shown that embelin binds to a small and charged groove aligned by hD, hF, s2A, and the hE-s1A loop in active Plasminogen activator inhibitor-1 (PAI-1) [129], located adjacent to the larger and deeper pocket inlatent PAI-1 that can be occupied by AZ3976 [128]
To address the lack of efficacy when translated into in vivo settings often encountered in high-throughput screening of large compound libraries, two filters were applied representing (I) the general drug-likeliness based on clinically used drug molecules, and (II) the specific lead-likeliness based on the reactive center loop (RCL) peptide P14-P10 as well as reference inhibitors that bind in the region of the vitronectin binding site in PAI-1 [219, 223]
Summary
Hemostasis is an essential physiological process that preserves the integrity of the vascular system and secures sufficient blood flow throughout the circulatory system. Through allosteric modulation of several regions remote from the SMB binding site, vitronectin causes a strong and widespread stabilization of the lower half of the PAI-1 molecule, including hB, hC, hD, hI, and the hIs5A loop, and induces conformational changes in the RCL without compromising the ability of PAI-1 to associate with PAs [99, 109, 110].
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