Newly Emerged Antiviral Strategies for SARS-CoV-2: From Deciphering Viral Protein Structural Function to the Development of Vaccines, Antibodies, and Small Molecules

Abstract

Coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most severe health crisis, causing extraordinary economic disruption worldwide. SARS-CoV-2 is a single-stranded RNA-enveloped virus. The process of viral replication and particle packaging is finished in host cells. Viral proteins, including both structural and nonstructural proteins, play important roles in the viral life cycle, which also provides the targets of treatment. Therefore, a better understanding of the structural function of virus proteins is crucial to speed up the development of vaccines and therapeutic strategies. Currently, the structure and function of proteins encoded by the SARS-CoV-2 genome are reviewed by several studies. However, most of them are based on the analysis of SARS-CoV-1 particles, lacking a systematic review update for SARS-CoV-2. Here, we specifically focus on the structure and function of proteins encoded by SARS-CoV-2. Viral proteins that contribute to COVID-19 infection and disease pathogenesis are reviewed according to the most recent research findings. The structure-function correlation of viral proteins provides a fundamental rationale for vaccine development and targeted therapy. Then, current antiviral vaccines are updated, such as inactive viral vaccines and protein-based vaccines and DNA, mRNA, and circular RNA vaccines. A summary of other therapeutic options is also reviewed, including monoclonal antibodies such as a cross-neutralizer antibody, a constructed cobinding antibody, a dual functional monoclonal antibody, an antibody cocktail, and an engineered bispecific antibody, as well as peptide-based inhibitors, chemical compounds, and clustered regularly interspaced short palindromic repeats (CRISPR) exploration. Overall, viral proteins and their functions provide the basis for targeted therapy and vaccine development.

Keywords: COVID-19; SARS-CoV-2; antibody treatment; compounds; inhibitors; nonstructural proteins; structural proteins; therapy; vaccines.

Figure 1

A schematic graphic of the genome-encoded proteins of SARS-CoV-2. (A) Genome-encoded nonstructural proteins from NSP1 to NSP16. (B) Genome-encoding proteins of SARS-CoV-2 with the structural proteins and nonstructural proteins. (C) Full length of S protein of SARS-CoV-2 comprised of subunit 1 (S1) and subunit 2 (S2). Abbreviations: bp: base pair; E: envelop protein; FP: fusion peptide; HR1 and HR2: heptad repeat regions 1 and 2; IC: intracellular tail; kb: kilobase pair; M: membrane protein; NSP: nonstructural protein; N: nucleocapsid protein; ORF1a: open reading frames 1a; ORF1b: open reading frames 1b; RBD: receptor-binding domain; S: spike protein; SP: signal peptide; S1: receptor-binding subunit; S2: membrane fusion subunit; TM: transmembrane; 5′-UTR: 5′-untranslated region; 3′-UTR: 3′-untranslated region.

Figure 2

The binding, entry, and package of SARS-CoV-2 in host cells. Genome-encoding proteins are labeled on an enlarged virus. There are two fusion pathways of viral protein with the host cell membrane, including (1) direct fusion with the cell membrane to release the virtual genome RNA and (2) endocytosis via membrane fusion of the viral membrane with a host cell membrane. hACE2: human angiotensin-converting enzyme 2; M: membrane protein; N: nucleocapsid protein; RdRp: RNA-dependent RNA polymerase; SARS-CoV-2: severe acute respiratory syndrome coronavirus-2; S: Spike protein; TMPRSS2: transmembrane serine protease 2.

Figure 3

Vaccines and pharmaceutical strategies against SARS-CoV-2 infection. The treatment options for COVID-19 infection are shown in cartoons. Current main treatment options against SARS-CoV-2 infection include (A) protein-based vaccines, (B) mRNA vaccines, (C) circular RNA vaccines, (D) nanoparticle antibodies, (E) engineered tetravalent bispecific antibodies, (F) peptide-based inhibitors (Protein Data Bank/PDB: 6M0J), and (G) chemical compounds (PDB: 7BV2). Abbreviations: ACE2: angiotensin-converting enzyme 2; CRISPR/Cas: clustered regularly interspaced short palindromic repeats–associated nucleases; RBD: receptor-binding domain.

Figure 4

Small molecules targeting spike protein and nonstructural proteins of SARS-CoV-2. Abbreviations: ACE: angiotensin-converting enzyme 2; NSP: nonstructural protein; PLpro: papain-like protease; RBD: receptor-binding domain; RdRp: RNA dependent RNA polymerase; 3CLpro: 3C-like protease.