Identification of intrinsically disorder regions in non-structural proteins of SARS-CoV-2: New insights into drug and vaccine resistance

Abstract

The outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 2019 and caused coronavirus disease 2019 (COVID-19), which causes pneumonia and severe acute respiratory distress syndrome. It is a highly infectious pathogen that promptly spread. Like other beta coronaviruses, SARS-CoV-2 encodes some non-structural proteins (NSPs), playing crucial roles in viral transcription and replication. NSPs likely have essential roles in viral pathogenesis by manipulating many cellular processes. We performed a sequence-based analysis of NSPs to get insights into their intrinsic disorders, and their functions in viral replication were annotated and discussed in detail. Here, we provide newer insights into the structurally disordered regions of SARS-CoV-2 NSPs. Our analysis reveals that the SARS-CoV-2 proteome has a chunk of the disordered region that might be responsible for increasing its virulence. In addition, mutations in these regions are presumably responsible for drug and vaccine resistance. These findings suggested that the structurally disordered regions of SARS-CoV-2 NSPs might be invulnerable in COVID-19.

An integrated understanding of the evolutionary and structural features of the SARS-CoV-2 spike receptor binding domain (RBD)

“…Since RBD contains substantial unstructured segments [85] , we then analyzed the preservation of the intrinsic disorder predisposition within the amino acid sequences of the evolutionarily closest Spike RBDs. The phylogenetic tree analysis as described above showed 15 most likely closest proteins retrieved from the aligned sequences (Supplementary Fig.…”

Hepatitis C Virus Infection and Intrinsic Disorder in the Signaling Pathways Induced by Toll-Like Receptors

“…These observations are in line with the well-known association between the protein intrinsic disorder and pathogenesis of various human diseases [ 81 , 207 , 208 , 209 , 210 , 211 , 212 ]. They also agree with the results of the comprehensive bioinformatics analyses of the prevalence of protein intrinsic disorder in various viruses such as human papillomaviruses (HPVs) [ 213 ], HCV [ 41 ], influenza viruses [ 214 ], HIV-1 [ 215 ], Dengue virus [ 216 ], respiratory syncytial virus (RSD) [ 217 ], Zika virus [ 218 , 219 ], Chikungunya virus [ 220 , 221 ], rotavirus [ 222 ], Japanese encephalitis virus [ 223 ], SARS-CoV-2 [ 224 , 225 ], human SARS and bat SARS-like coronaviruses [ 224 ], Middle East respiratory syndrome MERS coronavirus [ 226 , 227 ], and Chandipura virus [ 228 ] as well as in the interactomes of HPV [ 229 ] and HCV [ 40 ]. They are also supported by the results of the evaluation of intrinsic disorder in proteins involved in innate anti-viral immunity [ 230 ] and the comprehensive bioinformatics analysis of the global prevalence of intrinsic disorder in 6108 viral proteomes [ 231 ].…”

The Advantage Efficacy of Intranasal Live-Attenuated Vaccine Against SARS-CoV-2

“…In mice, another SARS-CoV vaccine candidate with simultaneous deletion of 8-12 amino acids in both the E and nsp1 genes C-termini improved IFN responses and reduced viral titers [35]. SARS-CoV and MERS-CoV mutations of non-structural protein 1 (nsp1), nsp16, and nsp14 have the potential to serve as attenuated live vaccines [36,37]. Both SARS-CoV-ExoN (-) and MERS-CoV-ExoN (-) are stable mutants that provide mice immunological protection despite their drastically reduced fidelity and moderate toxicity [38].…”