Role of Serine Proteases and Host Cell Receptors Involved in Proteolytic Activation, Entry of SARS-CoV-2 and Its Current Therapeutic Options

Figures & data

Figure 1 S glycoprotein of SARS-CoV-2 binds to host cell receptors (ACE2, TMPRSS2 and GRP78) found in human lung epithelial cells to facilitate entry mechanism of the virus. These host cellular receptors areexpressed in various tissues including human lung cells, kidney and gastrointestinal tract. The binding interaction of ACE2 to RBD region of S protein is a determinant factor for entry of the virus to host cell. Cleavage of S protein through host cell proteases is also required for further fusion of viral and host cell membrane. After the virus enters the host cell through receptor mediated endocytosis, cellular stress condition leads to the exportation of GRP78 for further activation and interaction of virus with host cell. The infection of virus is not limited to human epithelial cells of the lungs since ACE2 expressed in different tissues including kidneys, heart, liver, retina and enterocytes of the intestines and other tissues throughout the body. This indicates the possible tropism of virus in various tissues.

Note: Figure created with Biorender.com.Abbreviations: ACE2, angiotensin‑converting enzyme 2; GRP78, glucose regulated protein 78; RBD, receptor binding domain; TMPRSS2, transmembrane serine protease 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; S protein, spike glycoprotein.

Table 1 Assessment of Some Current Therapeutic Agents and Vaccine Development Trials for SARS-CoV-2

Intervention/Treatment	Status	Study Location	Targeting Mechanism of the Drug/Intervention	Conditions	NCT Number	References
Drugs
ER stress	Completed	Turkey	ER stress evaluated as GRP78 level elevated	COVID-19 and pneumonia	NCT4628637	^Citation36,Citation67
GRP78	Completed	Turkey	Serum protein level analysis	COVID-19 and endoplasmic reticulum	NCT4628637	^Citation67
ACEI/ARB	Active/not recruiting	USA, Utah	Block angiotensin-receptor and inhibit angiotensin converting enzyme-2	COVID-19 and Hypertension	NCT4467931	^Citation71
Camostat	Recruiting/phase I	USA, Connecticut	Inhibit protease activity of TMPRSS2	COVID-19	NCT4353284	^Citation83
Bicalutamide	Recruiting phase III	USA, Florida	Inhibit/block protease activity of TMPRSS2	COVID-19	NCT4509999	^Citation88
Vaccination
Synthetic MVA based SARS-COV-2 Vaccine	Recruiting Phase I	USA, California	Spike protein	COVID-19	NCT4639466	^Citation74,Citation75
Recombinant vaccination	Recruiting Phase I	China	Spike protein	COVID-19	NCT4636333	^Citation76,Citation77

Abbreviations: ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin-receptor blockers; ER, endoplasmic reticulum; GRP78, glucose regulated protein 78; MVA, modified Vaccinia virus Ankara; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

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