Potential Medical Application of Plasmin-Based Therapeutics

Abstract

Xinli Lin*, Wei Zhu, Yingjie Wang, Yu Cai, Xinyu Dong, Dongying Yang, Fangmei Tan, Zhiping Ma, Lanfen Li, Jiali Gao

Heart disease is the leading cause of death globally, and keeping hemostatic balance is essential for a healthy cardiovascular system. Disturbing the balance can cause major diseases, such as ischemic stroke, myocardial infarction, and SARS-CoV-2 caused systemic blood clotting. In vivo, the pathological thrombi are dissolved by the enzyme Plasmin (Plm), a serine protease derived from the proenzyme Plasminogen (Plg). Although the biological regulation of the Plg system has been intensively studied, the vast potential pharmaceutical applications of the Plm enzyme-based therapeutics are far from realized. This review focuses on the underemphasized direction of the therapeutic development of Plg, Plm, and Micro Plasmin (μ Plm), the catalytic domain of Plasmin. The major diseases can be treated with Plm-based thrombolytic therapeutics include thrombosis diseases, pulmonary fibrosis, and Alzheimer’s Disease. The review also describes a new approach of using a “directional structure-based protein engineering” for μ Plasmin based therapeutic drug development. In the Future Directions section, we will analyze the long-standing problem facing thrombolytic drug development, which is the often-fatal bleeding side effect. Contrary to the conventional approach of developing more stable, longer in vivo half-life protein or enzyme therapeutics, here we propose a new “hit and die” strategy, in which an “ideal” thrombolytic drug hits the targeting thrombi, dissolving them, and die out, avoiding bleeding side effect resulting from the continued activity of present thrombolytic drugs. In practice, we propose to develop unstable, short in vivo half-life thrombolytic therapeutics to reach good drug efficacy and at the same time, avoid bleeding side effect.

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