Newly Emerged Antiviral Strategies for SARS-CoV-2: Comparison
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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. The structure-function correlation of viral proteins provides a fundamental rationale for vaccine development and targeted therapy. 

  • COVID-19
  • SARS-CoV-2
  • nonstructural proteins
  • structural proteins
  • vaccines
  • therapy

1. Introduction of COVID-19

1.1. COVID-19 Pandemic

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious disease [1]. The outbreak of COVID-19 led to a global pandemic and resulted in tremendous loss with a high number of deaths (a total of 6,075,512 deaths, 20 March 2022) and infections (469,833,166 total confirmed cases, 20 March 2022) worldwide [2]. The COVID-19 disease causes more severe conditions for the immunocompromised population and accelerates the progression of other diseases [3]. The SARS-CoV-2 virus is a single-stranded enveloped positive-sense RNA virus that belongs to the β-coronavirus [4]. The proteins encoded by the genome of SARS-CoV-2 are comprised of structural (SPs) and nonstructural proteins (NSPs), as well as accessory proteins [5][6]. SPs mainly include spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins [7]. NSPs contain open reading frames (ORFs), including ORF1a and ORF1b regions. There are 16 NSPs located in the ORF1a and ORF1b regions [5]. A schematic of the genome-encoded proteins of SARS-CoV-2 is summarized in a figure (Figure 1).
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 source: https://doi.org/10.3390/ijms23116083.

2. Vaccine Approach to Prevent Infection

A vaccine is one of the most effective preventative strategies to prevent highly contagious infections, including COVID-19 infection. Here, we discuss strategies to develop vaccines based on viral components.

2.1. SARS-CoV-2 Inactivated Vaccines

2.1. SARS-CoV-2 Inactivated Vaccines

A viral vaccine is a vaccine that targets the whole virion, including the live-attenuated virus vaccine and inactive virus vaccine; both require the handling of viral infection agents for the purification of viruses to produce vaccines [8]. Live-attenuated vaccines have been successfully applied to protect against various diseases. However, the major disadvantage of their use is the potential reversion to gain virulence and become a disease-causing factor [9]. In contrast, an inactivated vaccine does not have the ability to revert to an unwanted state [10]. The whole inactivated SARS-CoV-2 virion that was generated in Vero cells has been used as an inactivated vaccine. The approved inactivated vaccines include the Sinopharm vaccine produced by the Beijing Institute of Biological Products Co., Ltd. (BIBP) (Beijing, China) [11][12], the Sinovac COVID-19 vaccine produced by Sinovac Life Sciences Co., Ltd. (Beijing, China) [13], and the COVAXIN vaccine developed by Bharat Biotech [14][15]. Vero cells have been applied to develop these vaccines. Other inactivated vaccines, such as the CovIran® vaccines investigated by Shifa Pharmed–Barkat, are waiting for clinical evaluation. The IMBCAMS vaccine is still under development [16]. There are many benefits of using inactivation technology for vaccine development as a traditional tool [17][18]. However, the development and production process of inactivated vaccines need more time due to the requirement for virus culture and inactivation procedure [19].

2.2. Protein-Based Vaccines

Protein-based vaccines do not require handling of the live and attenuated viruses. These kinds of vaccines are stable and easy to distribute. NVX-CoV2373, developed by NOVAVAX, belongs to protein-based vaccines. The vaccine is composed of a nanoparticle core, around which is the recombinant protein antigen of SARS-CoV-2, the sequence of spike (S) protein from the strain Wuhan-Hu-1 (Figure 32A). The vaccine nanoparticles are then mixed with Matrix-M™ adjuvant to produce the ready-to-use vaccine products. An immunology study showed that this vaccine can provoke host protection by inducing robust immune responses, including both cellular and humoral immunity [20]. A clinical trial showed the protection efficacy was 90% against multiple mutations such as variants Alfa, Beta, and Delta. This vaccine has been approved for emergency use for the prevention of COVID-19 in many countries [21]. Other protein subunit-based vaccines either are under investigation or in ongoing clinical trials.
Figure 32. 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 source: https://doi.org/10.3390/ijms23116083.

2.3. Nucleic Acid-Based Vaccines

2.3.1. DNA Vaccine

The nucleic-acid-based vaccines include DNA vaccines (e.g., DNA plasmids) and RNA vaccines. DNA vaccines do not contain any infectious pathogens. This is one of the safety advantages compared with weakened viral vaccines. DNA vaccines also have an advantage in stability compared with RNA vaccines [22]. Since the outbreak of COVID-19, different DNA-based vaccines have been explored and some of them put into clinical trials. According to the World Health Organization [16], most current DNA vaccines for SARS-CoV-2 are encoded for the S protein. However, there are differences in the vectors. For example, adenovirus ChAdOx1 is used as the vector for the AZD1222 Vaxzevria vaccine [23]. The adenovirus type 26 (Ad26) is utilized as a vector for the Janssen–Cilag International NV (Belgium) Ad26.COV2.S COVID-19 vaccine [24]. Human adenovirus has been applied as a vector for the development of the Sputnik V vaccine [25]. These aforementioned DNA vaccines have been approved for emergency use for the prevention of COVID-19. The adenovirus Type 5 Vector has also been used for the development of the Ad5-nCoV vaccine, which is under clinical trial evaluation [16].

2.3.2. mRNA Vaccine

The mRNA vaccine has received considerable attention as a powerful tool to combat against the COVID-19 pandemic. Compared with the traditional vaccines, mRNA vaccines have irreplaceable advantages. For instance, mRNAs are faster and easier to produce. As soon as the virus sequence is decoded, the development of mRNA vaccines can be initiated in a time-saving fashion. There is no need to handle highly infectious pathogens, such as viral isolation and culture. However, some challenges for the development of mRNA vaccines also exist. The mRNA is not as stable as the DNA vaccine and is extremely sensitive to high temperatures, which places difficulty on vaccine distribution. The shortness of the half-life is the innate feature of mRNAs. Thus, the nucleotide needs to be modified to enhance its stability. The uridine modifications to reduce the unfavored immunogenicity to hosts also need to be considered for mRNA vaccine development [26]. Upon the outbreak of COVID-19, two mRNA vaccines were developed and broadly used for disease protection, including BNT162b2 from BioNTech/Pfizer [27] and mRNA-1273 from Moderna [28]. Both vaccines are nucleoside-modified mRNAs encapsulated by lipid nanoparticles as delivery vectors (Figure 32B). They are designed based on stabilized prefusion of the SARS-CoV-2 S protein (the full-length S protein). Clinical trials results show the protection efficacies of BNT162b2 (ClinicalTrials.gov, NCT04368728) [27] and mRNA-1273 (ClinicalTrials.gov, NCT04470427) [28] against SARS-CoV-2 infection were 95% and 94.1%, respectively.

3. Antiviral Antibodies

Therapeutic antibodies for SAR-CoV-2 include a monoclonal antibody (mAb) and a cocktail of several monoclonal antibodies. Some antibodies are developed to block the binding site of the virus to the host. Others are developed for inflammatory modulation.

3.1. Monoclonal Antibody

3.1.1. Monoclonal Antibody from Human Patients

Bebtelovimab (LY-CoV1404) is a mAb that neutralizes the SARS-CoV-2 spike glycoprotein RBD. It is a human immunoglobulin G-1 (IgG1) mAb. In vitro studies showed that it retained the binding to S proteins with a broad range of virus variants. Clinical evaluation on the effect of Bebtelovimab alone or together with other monoclonal antibodies Bamlanivimab and Etesevimab is ongoing [29][30]. It has been recommended as an alternative option for managing COVID-19 only when the preferred small molecules Ritonavir-boosted nirmatrelvir and Remdesivir are not available.

3.1.2. Nanoparticle Antibody

Recently, Wu et al. characterized some RBD-specific neutralizing nanobodies and selected a nanobody library derived from alpaca immunization with the SARS-CoV-2 spike glycoprotein. The identified nanobodies showed a neutralizing function against the wild-type and Delta variants of SARS-CoV-2, which are specifically bound with a virus antigen [31]. Then, they also engineered a combined nanoparticle antibody using two nanobodies and a linker (Figure 32D), which showed a significantly increased neutralizing effect compared with every single particle [31]. These findings highlight the possibility of exploring the antibody from different sources and using multiple nanobodies.

3.2. Antibody Cocktail

Due to the rapid mutation of viruses, the efficacy of mAbs is influenced. Thus, a cocktail of two or multiple antibodies may confer a powerful neutralizing effect against viral variants. Antibody cocktails for SARS-CoV-2 such as a cocktail of Tixagevimab plus Cilgavimab have been issued by FDA for emergency use against COVID-19 infection [32]. This cocktail also showed a neutralizing effect on Delta and Omicron variants [33][34]. There are many ongoing and finished studies for the efficacy evaluation of antibody cocktails. Some new approaches are worthy to specifically point out. One study reported a novel approach using protein structures to guide the design of antibody cocktails. The development of structure-guided antibody cocktails displays some great advantages. Some of these cocktails showed potent neutralizing ability against all the variants such as Alpha, Beta, Gamma, Epsilon, Iota, Kappa, and Delta in mouse and hamster models [35][36]. These cocktails hold promise and the potential to become one of the useful tools to combat viral infection, especially for the infection caused by highly mutated variants.

3.3. Engineered Bispecific Monoclonal Antibody

A recent study reported a bispecific single-domain antibody, named bn03. It was designed based on the highly conserved region of RBD of Omicron variants. Interestingly, the bispecific bn03 showed a significantly higher naturalization efficacy compared with the cocktail combination of n3113v and n3130v. The EM-crystal structure analysis of Omicron (S-bn03) showed that it includes two arms, and both arms can simultaneously bind with the single RBD. The synergistic effect conferred by the two arms of bn03 increased the binding affinity of antibodies to viruses. Therefore, the neutralization effect of bn03 was increased. In addition, due to its small size, bn03 was able to bind to the most conserved cryptic epitopes in the deeper binding site. Moreover, the team verified that inhalation is the best method for bn03 delivery compared with other delivery paths [37]. Although there are some limitations such as limited sample numbers, this well-designed study still provides uresearchers positive inspiration for using a similar approach to engineer antibodies for virus treatment. In another study, two different bispecific antibodies were generated using a distinct design and were compared with their parental antibodies and their cocktails. One is tetravalent bispecific antibody 14-H-06, and another is a bivalent bispecific antibody 14-crs-06. Both in vitro and in vivo studies demonstrated that 14-H-06 coffered a significantly higher neutralization potency compared with 14-crs-06 (Figure 23E). Both bispecific (tetravalent and bivalent) antibodies showed greater efficacy compared with their parent antibodies or their cocktail [38]. Thise study illustrates that using an engineered bispecific antibody is a strategy to improve the efficacy of the parental antibody.
Figure 3. 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.

4. Peptide-Based Inhibitor

Small peptides can be designed and used as inhibitors to prevent the infection of viruses and other infectious pathogens [39][40]. For example, the N-terminal helix of the hACE2 contains the amino acids that mediated the interaction of hACE2 with the virus. This sequence has been used as a model to generate peptides that mimic the hACE2 (Figure 3F) [41]. The de novo design of miniprotein or peptides targeting the RBD binding site showed both increased binding affinity and enhanced stability. In the same study, the computationally generated scaffolds were also designed to stay around the ACE2 helix and interact with the virus RBD. In such a way, the scaffolds can block the direct interaction between ACE2 and virus RBD. The stability of the binding was further confirmed by the Cryo-EM structure [42]. Using the above-mentioned methods to design small peptides or miniproteins is another strategy to develop pharmaceutical medicines for viral infection (Figure 32F).

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