Coronavirus Disease (COVID-19) Control between Drug Repurposing and Vaccination: A Comprehensive Overview

Abstract

Respiratory viruses represent a major public health concern, as they are highly mutated, resulting in new strains emerging with high pathogenicity. Currently, the world is suffering from the newly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus is the cause of coronavirus disease 2019 (COVID-19), a mild-to-severe respiratory tract infection with frequent ability to give rise to fatal pneumonia in humans. The overwhelming outbreak of SARS-CoV-2 continues to unfold all over the world, urging scientists to put an end to this global pandemic through biological and pharmaceutical interventions. Currently, there is no specific treatment option that is capable of COVID-19 pandemic eradication, so several repurposed drugs and newly conditionally approved vaccines are in use and heavily applied to control the COVID-19 pandemic. The emergence of new variants of the virus that partially or totally escape from the immune response elicited by the approved vaccines requires continuous monitoring of the emerging variants to update the content of the developed vaccines or modify them totally to match the new variants. Herein, we discuss the potential therapeutic and prophylactic interventions including repurposed drugs and the newly developed/approved vaccines, highlighting the impact of virus evolution on the immune evasion of the virus from currently licensed vaccines for COVID-19.

Keywords: COVID-19; SARS-CoV-2; clinical trials; drug repurposing; management; vaccines.

Figure 1

The schematic diagram illustrates the life cycle of coronavirus. The spike (S) protein of coronavirus commences infection “endocytosis” via recognizing the cellular ACE2 receptors and binding to it with its receptor-binding domain (RBD) in the S1 subunit. Following the viral genome (+ssRNA) into the host cell cytoplasm, two long polyproteins, namely pp1a and pp1ab, are translated from viral ORF1a and ORF1ab transcripts. The pp1a and pp1ab are further cleaved into 16 essential nonstructural proteins (NSPs). Necessary elements to the viral genome replication/transcription (e.g., nsp-7, nsp-8, and nsp-12) are congregated as RNA replication–transcription complexes (RTCs) inside ER-derived double-membrane vesicles (DMVs) to initiate the transcription/replication machinery for the internalized +ssRNA genome, leading to the generation of the genomic and subgenomic RNAs and their encoded viral proteins. Following the assembly of the posttranslated viral proteins and the nascent genomic RNA, the budding virion is then released from the infected host cell via exocytosis. Figure has been created by microsoft powerpoint.

Figure 2

Drug repurposing for fighting COVID-19 and the introduction of different types of vaccines for prophylaxis. Figure has been created using BioRender.com.

Figure 3

Schematic representation of the cellular innate responses against SARS-CoV-2 virus. Following the recognition of the viral PAMPs by PRRs, the downstream signaling molecules are activated. The PRR on the epithelial host cell are transmembrane localized Toll-like receptors (TLRs) and the cytosolic RIG-I-like receptors, which include the helicases: RIG-I (retinoic acid-inducible gene I), and MDA-5 (melanoma differentiation-associated gene 5). The PAMP ligand for RIG-I-like receptors is specific viral ssRNA structures with 5′-triphosphate termini (5′ppp) or long dsRNA. The TLR-3 and TLR-7 signaling pathways are subsequently activators for the IFN regulatory factors (IRFs) and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF–kB), leading to proinflammatory cytokine and type-I IFN production. Following their expression, type-I IFNs induce a variety of signal transduction pathways by targeting different signaling receptors on the neighboring cell. Secreted IFN binds to a heterodimeric transmembrane receptor, composed of the subunits IFNAR1/2, to catalyze the dimerization of the IFNAR1 and IFNRA2 chains of the receptor. This dimerization stimulates the autophosphorylation of the receptor-associated tyrosine-protein kinase 1 (JAK1) and tyrosine kinase 2 (Tyk2). Subsequently, the JAK1/Tyk2 phosphorylates the downstream substrates STAT1 and STAT2. To form the essential heterotrimeric transcriptional factor complex IFN-stimulated gene factor 3 (ISGF3), active/phosphorylated STAT1 and STAT2 engage the IFN regulatory factor IRF9 in the cytoplasm. Furthermore, the ISGF3 complex localizes in the nucleus to bind the cis-element of the IFN-stimulated response element (ISRE) and stimulate the transcription of plenty of antiviral ISGs. Figure has been created using BioRender.com.