Understanding Individual SARS-CoV-2 Proteins for Targeted Drug Development against COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic, responsible for millions of deaths globally. Even with effective vaccines, SARS-CoV-2 will likely maintain a hold in the human population through gaps in efficacy, percent vaccinated, and arising new strains. Therefore, understanding how SARS-CoV-2 causes widespread tissue damage and the development of targeted pharmacological treatments will be critical in fighting this virus and preparing for future outbreaks. Herein, we summarize the progress made thus far by using in vitro or in vivo models to investigate individual SARS-CoV-2 proteins and their pathogenic mechanisms. We have grouped the SARS-CoV-2 proteins into three categories: host entry, self-acting, and host interacting. This review focuses on the self-acting and host-interacting SARS-CoV-2 proteins and summarizes current knowledge on how these proteins promote virus replication and disrupt host systems, as well as drugs that target the virus and virus interacting host proteins. Encouragingly, many of these drugs are currently in clinical trials for the treatment of COVID-19. Future coronavirus outbreaks will most likely be caused by new virus strains that evade vaccine protection through mutations in entry proteins. Therefore, study of individual self-acting and host-interacting SARS-CoV-2 proteins for targeted therapeutic interventions is not only essential for fighting COVID-19 but also valuable against future coronavirus outbreaks.

Keywords: COVID-19; Nsp1; Nsp6; Orf3a; Orf6; Orf7a; SARS-CoV-2; drug development; individual virus proteins; virulence factors; virus-host interactions.

FIG 1

SARS-CoV-2 protein functions and host interactions. Shown is a graphic representation of the SARS-CoV-2 proteome. Boxes connected to proteins indicate the virus transcription and translation functions (italics) (summary of Table 1) and known human protein interaction with their effect on human pathways (summary of Table 2). Abbreviations: 3CLpro, 3-chymotrypsin-like protease; 7SL, RNA component of SRP ribonucleoprotein complex; ACE2, angiotensin I-converting enzyme 2; eIFs, eukaryotic translation initiation factors; ExoN, exoribonuclease; HOPS, homotypic fusion and protein sorting complex; IFN, interferon; IRF3, interferon regulatory factor 3; ISG, interferon-stimulated gene; KPNA2, karyopherin alpha 2; MAVS, mitochondrial antiviral-signaling protein; Mpro, main protease; NEMO, NF-κB essential modulator; NLRP12, NLR family pyrin domain containing 12; NUP98, nuclear pore complex protein 98; NXF1, nuclear RNA export factor 1; PARPs, poly(ADP-ribosyl) polymerases; PIC, ribosomal preinitiation complex; PLpro, papain-like protease; RAE1, RNA export 1; RdRp, RNA-dependent RNA polymerase; RIG-I, retinoic acid-inducible gene I; SRP, signal recognition particle; TAB1, TGF-β-activated kinase 1 (MAP3K7) binding protein 1; TBK1, TANK binding kinase 1; TMPRSS2, transmembrane serine protease 2; TOM70, translocase of outer membrane 70 (subunit of mitochondrial import receptor); VPS39, vacuolar protein sorting 39 (subunit of HOPS complex).