TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections

Abstract

Influenza virus and coronavirus epidemics or pandemics have occurred in succession worldwide throughout the early 21st century. These epidemics or pandemics pose a major threat to human health. Here, we outline a critical role of the host cell protease TMPRSS2 in influenza virus and coronavirus infections and highlight an antiviral therapeutic strategy targeting TMPRSS2.

Keywords: Coronavirus; Influenza virus; TMPRSS2; Therapeutics.

Fig. 1

A schematic diagram of TMPRSS2 genomic location.

Fig. 2

The location and structure of TMPRSS2 protein. TM: transmembrane domain; LDLRA: low-density lipoprotein receptor domain class A; SRCR: Scavenger receptor cysteine-rich domain; Letters H: histidine; Letters D: aspartate; Letters S: serine.

Fig. 3

Structure of influenza hemagglutinin and coronavirus spike protein with cleavage sites. Arrows: cleavage site; FP: putative fusion peptide; TM: transmembrane domain; S-S: disulfide bond.

Fig. 4

Membrane fusion mediated by hemagglutinin. A) Viral membrane with two representative cleaved neutral pH HA and endosome membrane. B) The acidic environment of the endosome inducing conformational changes results in fusion peptide exposure and insertion into the target membrane. C) Conformational changes drive the viral and cellular membranes close proximity. D) Formation of pre-fusion stalk intermediate. E) Formation of hemifusion intermediate. F) Formation of fusion pore and viral genome is released into the cytoplasm. The Figure is adapted according to Karen J. Cross .

Fig. 5

The replication cycle of influenza virus and the proteolytic cleavage of the host proteases. Influenza virus binds to sialic acid-containing cell surface receptors, the bound virus is then endocytosed. During maturation of the endosome, the pH drops initiates the fusion of the viral envelope with the endosomal membrane and the release of the vRNPs into the cytosol. The vRNPs are imported into the nucleus, then transcription and replication proceed. Translation of viral mRNAs is performed by the cellular machinery. Newly formed viral RNAs are exported to the cytosol, assembled with new virus structural proteins, then packaged together at the plasma membrane, and bud off to release new virions. HA is synthesized as precursor that requires cleavage. HA cleavage by membrane-bound proteases (indicated as scissors) can take place in different part and at different time points during the viral life cycle. HA containing a monobasic cleavage site is cleaved by TMPRSS2 in the Golgi apparatus during assembly or cleaved by HAT on the plasma membrane either during attachment and entry into the cell or during budding of virions.

Fig. 6

The replication cycle of coronavirus and the proteolytic cleavage of the host proteases. Coronavirus binds to the cellular receptor, resulting in uptake of virions into endosomes (route 1), where the spike protein is activated by cathepsin. The pH drops in endosome initiates the fusion of the viral envelope with the endosomal membrane and the release of the viral genetic material into the cytosol, then RNA transcription, replication and transcription take place. New viral RNA is transported to the endoplasmic reticulum, Golgi intermediate, the site of assembly. Viral RNA and structural proteins assemble and bud into vesicles. Vesicles are transported to the cell surface and release. Alternatively, the spike protein can be activated at the cell surface, resulting in fusion of the viral membrane with the plasma membrane (route 2). Spike is synthesized as precursor that requires cleavage by host proteases. Spike cleavage (indicated as scissors) can take place in different part and at different time points during the viral life cycle. Spike cleavage by cathepsin occurs in the endosome. Spike cleavage by TMPRSS2 takes place in the Golgi or plasma membrane, either during assembly or attachment and release.

Fig. 7

Structures of some small molecular inhibitors for TMPRSS2 and TMPRSS2-related agents.