Targeting Crucial Host Factors of SARS-CoV-2

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide since its first incidence in Wuhan, China, in December 2019. Although the case fatality rate of COVID-19 appears to be lower than that of SARS and Middle East respiratory syndrome (MERS), the higher transmissibility of SARS-CoV-2 has caused the total fatality to surpass other viral diseases, reaching more than 1 million globally as of October 6, 2020. The rate at which the disease is spreading calls for a therapy that is useful for treating a large population. Multiple intersecting viral and host factor targets involved in the life cycle of the virus are being explored. Because of the frequent mutations, many coronaviruses gain zoonotic potential, which is dependent on the presence of cell receptors and proteases, and therefore the targeting of the viral proteins has some drawbacks, as strain-specific drug resistance can occur. Moreover, the limited number of proteins in a virus makes the number of available targets small. Although SARS-CoV and SARS-CoV-2 share common mechanisms of entry and replication, there are substantial differences in viral proteins such as the spike (S) protein. In contrast, targeting cellular factors may result in a broader range of therapies, reducing the chances of developing drug resistance. In this Review, we discuss the role of primary host factors such as the cell receptor angiotensin-converting enzyme 2 (ACE2), cellular proteases of S protein priming, post-translational modifiers, kinases, inflammatory cells, and their pharmacological intervention in the infection of SARS-CoV-2 and related viruses.

Keywords: COVID-19; SARS-CoV-2; coronavirus; drug targets; host factors; inhibitors.

Figure 1:. Potential host factors as drug targets in the SARS-CoV-2 life cycle.

The studies on SARS-CoV and other coronaviruses have helped to predict the lifecycle of SARS-CoV-2. The SARS-CoV-2 attaches to the cell surface receptor ACE2 by its spike protein ^,–, which is cleaved by cell surface proteases such as TMPRSS2, furin, and TMPRSS4, TMPRSS11^, initiating cell entry. Various host kinases, including (Abelson tyrosine kinases) Abl2 and phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase (PIKfyve), are involved in the membrane/intracellular trafficking of SARS-CoV-2 ^,. When the virus is taken up into endosomes, cathepsin L also can prime spike protein. In SARS-CoV, upon release of viral RNA into the cytoplasm, open reading frames (ORF)1 and ORF2 are translated to polyproteins pp1a and pp1ab. These polyproteins are then cleaved by virally encoded chymotrypsin-like proteases (3CLpro) and papain-like proteases (PLpro) to give 16 non-structural proteins (Nsps) forming an RNA replicase–transcriptase complex . The copies of negative RNA are produced, and using this as a template, positive RNA is produced in the replication process. Through discontinuous transcription, 7-9 subgenomic RNAs are produced . The viral nucleocapsids are assembled from genomic RNA and N protein in the cytoplasm. Post-translational modifications such as glycosylation happen in the endoplasmic reticulum (ER) and the Golgi complex. After budding of the virions into the lumen of the ER–Golgi intermediate compartment (ERGIC) of infected cells, they are released by exocytosis. The cleavage of the spike protein of the newly released virions also can happen at the cell surface.

Figure 2:. Comparison of the S protein of SARS-CoV and SARS-CoV-2 ^,.

Basic amino acid residues are in red color text. S1: spike subunit 1; S2: spike subunit 2; RBD: receptor-binding domain; RBM: receptor-binding motif; TMD: transmembrane domain.

Figure 3:

Human TMPRSS2 . The extracellular domain includes a serine protease domain (aa 255-492), a scavenger receptor cysteine-rich domain (SRCA, aa 149-242), and LDL receptor class A (LDLRA, aa 113-148) having a binding site for calcium. The figure also shows the transmembrane domain (TMD, aa 84-106) and cytoplasmic domain (aa 1-84). Histidine (H), aspartate (D) and serine (S) are the three catalytic residues; attached numbers indicate their positions.