Host Proteases and Coronavirus Invasion： From S Protein Cleavage Mechanism to Development and Applications of Protease Inhibitor

doi:10.13560/j.cnki.biotech.bull.1985.2025-0826

Abstract

Abstract:

Coronaviruses, a class of RNA viruses, demonstrate a broad host range, infecting various mammals and birds. The process by which these viruses invade host cells is closely associated with the spike (S) protein. This major glycoprotein, located on the surface of the virus, consists of two subunits: S1 and S2. The S1 subunit is responsible for recognizing and binding to the host cell receptor, while the S2 subunit undergoes conformational rearrangement following cleavage by host protease. This rearrangement facilitates the fusion of the virus with cell membrane, thereby enabling invasion. Different coronaviruses feature distinct motifs on their S proteins that serve as recognition sites for various host proteases such as transmembrane serine protease 2 (TMPRSS2), Furin, cathepsin L/B (CTSL/B), and trypsin. The molecular characteristics and activation mechanisms of these protease cleavage sites vary, influencing the virus’s invasion routes and infection efficiency in the host cells. Variations in expressions and activities of host proteases across different tissues or cell types significantly affect the tissue tropism and transmission routes of the virus. Protease inhibitors targeting these host proteases can effectively impede virus invasion and transmission, representing a crucial focus in current anti-coronavirus drug development. This paper systematically reviews the molecular characteristics of key cleavage sites in the S proteins of various coronaviruses, investigates the activation mechanisms of distinct host proteases, and discusses the development strategies for protease inhibitors aimed at these proteases, along with their potential applications in antiviral therapy. By analyzing this critical mechanism, this review aims to offer theoretical support for a deeper comprehension of coronaviruses’ pathogenic mechanisms and to provide a scientific foundation for designing and developing novel antiviral medications.

Key words: coronavirus, S protein, cleavage site, host protease, protease inhibitor

JIANG Yi, GAO Ming-yan, ZHANG Di, FU Li-xia, CHENG Xu, CHEN Xiang, GONG Jian-sen, ZHANG Ying, YANG Qin, YU Yan. Host Proteases and Coronavirus Invasion： From S Protein Cleavage Mechanism to Development and Applications of Protease Inhibitor[J]. Biotechnology Bulletin, 2026, 42(2): 121-135.

Figures/Tables 4

References 71

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蛋白酶 Protease	细胞定位 Cellular localization	作用途径 Pathway	识别基序 Recognized motif P2-P1↓P1′-P2′	是否依赖酸性环境 Acid dependence	参考文献 References
Furin	TGN	生物合成	RXK/RR↓S	不依赖	［20-21］
TMPRSS2	跨膜	质膜途径	K/R↓S	不依赖	［22］
CTSL/B	内质体/溶酶体	内体途径	R/K/G/A/S/T/Q/Y↓	依赖，pH 3.0-6.5	［18， 23-24］
HAT	跨膜	质膜途径	K/R↓	不依赖	［25］
胰蛋白酶	细胞外	质膜途径	选择性不高，主要K/R↓S	中性pH值，最适pH 8.0	［26］
弹性蛋白酶	细胞外	质膜途径	A/S/G/V/W/Y/F/L/C/M↓	不依赖	［27-28， 85］
纤溶酶	细胞外	质膜途径	K/R↓	不依赖	［29］

蛋白酶 Protease	细胞定位 Cellular localization	作用途径 Pathway	识别基序 Recognized motif P2-P1↓P1′-P2′	是否依赖酸性环境 Acid dependence	参考文献 References
Furin	TGN	生物合成	RXK/RR↓S	不依赖	［20-21］
TMPRSS2	跨膜	质膜途径	K/R↓S	不依赖	［22］
CTSL/B	内质体/溶酶体	内体途径	R/K/G/A/S/T/Q/Y↓	依赖，pH 3.0-6.5	［18， 23-24］
HAT	跨膜	质膜途径	K/R↓	不依赖	［25］
胰蛋白酶	细胞外	质膜途径	选择性不高，主要K/R↓S	中性pH值，最适pH 8.0	［26］
弹性蛋白酶	细胞外	质膜途径	A/S/G/V/W/Y/F/L/C/M↓	不依赖	［27-28， 85］
纤溶酶	细胞外	质膜途径	K/R↓	不依赖	［29］