Host Cell and SARS-CoV-2-Associated Molecular Structures and Factors as Potential Therapeutic Targets

Abstract

Coronavirus disease 19 (COVID-19) is caused by an enveloped, positive-sense, single-stranded RNA virus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the realm Riboviria, order Nidovirales, family Coronaviridae, genus Betacoronavirus and the species Severe acute respiratory syndrome-related coronavirus. This viral disease is characterized by a myriad of varying symptoms, such as pyrexia, cough, hemoptysis, dyspnoea, diarrhea, muscle soreness, dysosmia, lymphopenia and dysgeusia amongst others. The virus mainly infects humans, various other mammals, avian species and some other companion livestock. SARS-CoV-2 cellular entry is primarily accomplished by molecular interaction between the virus's spike (S) protein and the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), although other host cell-associated receptors/factors, such as neuropilin 1 (NRP-1) and neuropilin 2 (NRP-2), C-type lectin receptors (CLRs), as well as proteases such as TMPRSS2 (transmembrane serine protease 2) and furin, might also play a crucial role in infection, tropism, pathogenesis and clinical outcome. Furthermore, several structural and non-structural proteins of the virus themselves are very critical in determining the clinical outcome following infection. Considering such critical role(s) of the abovementioned host cell receptors, associated proteases/factors and virus structural/non-structural proteins (NSPs), it may be quite prudent to therapeutically target them through a multipronged clinical regimen to combat the disease.

Keywords: SARS-CoV-2; angiotensin-converting enzyme 2; coronavirus disease 19; pathogenesis; therapeutic targeting.

Figure 1

Host cell receptor/molecules/factors as therapeutic targets for FDA-approved drug repurposing. Broadly, therapeutic approaches can be designed by keeping in consideration three categories of host cell molecules: (a) receptor(s) such as ACE2 and neurophilin (NPR) facilitating cellular entry of SARS-CoV-2, (b) associated factors/proteases mediating receptor priming and cleavage, and (c) SARS-CoV-2: host cell protein–protein interaction (interactome).

Figure 2

Interactome, involving SARS-CoV-2 proteins and cellular proteins. SARS-CoV-2 structural and non-structural proteins have been found to interact with multiple host cell proteins involved in various cellular processes, as well as remain associated with several cell organelles. SARS-CoV-2 proteins are shown in the center of the small circle, whereas human host cell proteins are placed in the center of the large circle. An arrow indicates a possible interaction, which may or may not have significant implications. N-Neucleocapsid protein, S-Spike protein, M-Membrane protein and E-Envelope protein.

Figure 3

Potential targets on SARS-CoV-2. SARS-CoV-2, the causative organism of COVID-19, possesses four types of structural proteins, namely spike (S), membrane (M), envelope (E), and nucleocapsid (N). Of these, the homotrimeric S protein shows the highest immunogenicity, leading to the production of correspondingly high amount of the anti-S antibody, and generation of memory B and T cells. Anti-M, anti-N and anti-E antibodies, albeit in lesser quantities, are also detected in samples derived from COVID-19 patients.