The 249RWMD spike protein insertion in Omicron BQ.1 subvariant compensates the 24LPP and 69HV deletions and may cause severe disease than BF.7 and XBB.1 subvariants

Chakraborty, A. K.

doi:10.21203/rs.3.rs-2488250/v1

Cited by 8 publications

(9 citation statements)

References 44 publications

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“…OQ075400) (Habib et al 2023). Interestingly, we also recently pinpointed round 400 147 RWMD spike insertion mutants in US patients (Chakraborty, 2023a). We found three Northern Ireland (UK) based patients where such RWMD insertion was observed (accession numbers; OX527225, OX520545, OX486753).…”

Section: Resultsmentioning

confidence: 74%

Highly infectious, less pathogenic and antibody resistant Omicron XBB.1, XBB.1.5 and XBB.1.5.1-XBB.1.5.39 subvariant Coronaviruses do not produce ORF8 protein due to 8th codon GGA=TGA Termination Codon Mutation

Chakraborty

2023

Preprint

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RNA viruses are very mutation prone. We recently reported SARS-CoV-2 ORF8 gene CAA = TAA and AAA = TAA Termination Codon Mutations in B.1.1.7 variants with no production of viable ORF8 protein. We described here another GGA = TGA termination codon in the 8th codon of ORF8 gene located exclusively in XBB.1 (XBB.1.16 and XBB.1.22) and XBB.1.5 subvariants (XBB.1.5.1 to XBB.1.5.39) but not in XBB.2 variant or Alpha, Beta, Gamma, Delta and Omicron BA.1, BA.2, BA.4, BA.5, BF.7 and BQ.1 subvariants. However, G > T mutation at 27915 also created an alternate ATG codon but the protein product was short due to preceding TAG and TGA termination codons. The originally located following ATG codons were there but in alternate reading frames and ultimately no ORF8 protein was formed in XBB.1.5 subvariants which were spreading highly now over BA.2.75, BA.4.6, BA.5.2.1, BF.7 and BQ.1.1 subvariants. This is a vivid example of three termination codon mutations in the coronavirus ORF8 protein which was implicated as target for many human proteins regulating interferon production, chromosome instability, antibody production, pathogenicity and virus clearance. The 30nt deletion in the 3’-UTR, including 24LPP, and 145Y deletions in Spike protein as well as N-protein 31ERS and ORF1ab polyprotein 3675SGF deletions made XBB.1.5 Omicron coronavirus weak and less pathogenic so that WHO declared coronaviruses as non-emergency pathogen.

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Section: Resultsmentioning

confidence: 74%

Highly infectious, less pathogenic and antibody resistant Omicron XBB.1, XBB.1.5 and XBB.1.5.1-XBB.1.5.39 subvariant Coronaviruses do not produce ORF8 protein due to 8th codon GGA=TGA Termination Codon Mutation

Chakraborty

2023

Preprint

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“…While BA.5 has been the dominant strain since the end of 2022, variants such as BQ.1.1, strain derived from BA.5 and XBB strain derived from BA.2 have been emerging (119)(120)(121)(122)(123)(124)(125).…”

Section: Discussionmentioning

confidence: 99%

Rapid screening methods for universal binding peptide aptamers against SARS-CoV-2 variant spikes, including omicron variants, and their application to diagnostic and therapeutic agents.

Hayashi

2023

Preprint

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The development of mRNA vaccines and oral drugs against SARS-CoV-2 has been useful in protecting against Covid-19 infection. Since then, however, many variants of delta and omicron strains with enhanced infectivity and immune escape capacity have emerged. A 7-amino acid random peptide ribosome display library screening system was used to perform a rapid in vitro screening of peptide aptamers that universally bind to the SARS-CoV-2 wild-type, delta, and Omicron variant BA.1, BA.2, and BA.5 spike RBD (Receptor Binding Domain). Screening resulted in four peptide aptamers that showed positive binding reactions in ELISA. Interestingly, Amino Acid Sequence Determination of the four clones predicted that three of the four clones contain 2 ~ 3 Cys residues in their sequences, forming a complex higher-order structure with disulfide (S-S) bonds. The 7-amino acid random peptide ribosome display library screening system allows for rapid in vitro screening of peptide aptamers that bind to other unknown emerging infectious disease pathogens that may be pandemic in the future. The peptide aptamers are as small as 30 amino acids and can be easily synthesized and purified as peptides or proteins, or simply used as mRNA drugs.

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“…Data analysis detected one amino acid deletion ( 140 Y=TAT; 145 Y in B.0) in spike in BA. 4 (37). The spike N460K and K444T mutations in BQ.1 may be important driving force for immune-escape similar to F486S and N480K mutations in BA.2.75 subvariant and related XBB.1 subvariant.…”

Section: Introductionmentioning

confidence: 99%

“…In August 2023, we detected more than 448 249 RWMD spike insertion sequences spread in the USA and Europe. But such lineage was not prominent at the end of 2023 (37). Where as in December 2023 new sub-subvariants like XBB.1.16, XBB.1.5, EG.5.1, HV.1, FL.1.5, JN.1 and JD.1.1 were the major omicron coronaviruses sequences were deposited in the NCBI virus database (29,30).…”

Section: Introductionmentioning

confidence: 99%

Higher Omicron JN.1 Coronavirus Transmission due to Unique 17MPLF Spike Insertion compensating 24LPP, 69HV, 145Y, 211N and 483V deletions in the spike

CHAKRABORTY

2024

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The COVID-19 Spike protein 24LPP, 69HV, 143VYY, 156FR, 212L deletions, 215EPE and 249RWMD insertions were very well characterized. Changes in spike likely select RBD in a favorable 3-D structure to interact with ACE-2 receptor of human cells for coronavirus entry. Our goal is to characterize the newly spreading JN.1 subvariant and related omicron coronaviruses. BLASTP search found a 17MPLF four amino acid insertion in omicron BA.2.86 subvariant and its precedent JN.1 subvariant which had unique L452S (L455 in Wuhan) spike mutation. The JN.1 variant also contained 2375SGF deletion in ORF1ab, 24LPP, 69HV, 145Y, 211N (208N in BA.2) and 483V (480V in BA.2) deletions in the spike, 31ERS deletion in N-protein and 26nt deletion in 3’-UTR (NC_045512.2). Many unique JN.1 spike mutations (242N = H249N, 261D = A268D, 352T = K360T, 400K = R407K, 442H = P449H, 449W = L456W, 474K = N485K, 480K = A488K and 566V = A574V) might be also important. The BLASTN search with insertion oligo found over 3895 JN.1 related sequences in the NCBI Database and were well distributed in America and Europe but more monopartite JN.1 sequences deposited from Europe. Although, JN.1 acquired the 69HV deletion lately but did not generated from BA.4 or BA.5 lineages and it was solely generated from BA.2.86 variant. Swiss-Model detected a wing structure with basic amino acid in the middle of tripartite spike of JN.1 and important ACE-2 first interacting surface amino acids were changed. The small M protein of JN.1 had D3H, A63T and A104V mutations but Swiss Model showed no gross change in 3-D structure. Further, four JN.1 specific ORF1ab polyprotein mutations were detected: T170I mutation in nsp1 as well as D1600N, K1973R mutations in nsp3 protease and R3821K mutation in nsp6. Astonishingly, after a long journey of XBB.1.5.1 to XBB.1.5.100 subvariants spread, a sudden five amino acids deletion (176EGKEG and180EGKQG in Wuhan) in the spike of XBB.1.5.103 subvariant was found. The ORF8 immune-regulatory protein expression was abolished in all XBB.1 subvariants including XBB.1.5.103 and XBB.1.16.23 as expected due to termination codon mutations (AAA = TAA, CAA = TAA, GGA = TGA). But such ORF8 gene mutation (GGA = TGA) was also found in ongoing dominated JD.1.1, FL.1.5.1, HV.1 and EG.5.1.1 subvariants, derived from XBB.1 lineage. The FL.1.5.1 variant also has 82GHV deletion instead 82GHVMV in the nsp1 protein as well as a 27nt deletion (27887 5’-aac gaa cat gaa att tct tgt ttt ctt-3’) in the ORF7a gene. Partial or no expression of nsp1, ORF7a and ORF8 regulatory proteins cause coronavirus more immune deficient and less pathogenic. The spread of JN.1 has sent an alarm among health officials worldwide. It is worthwhile to see if JN.1 coronavirus goes nsp1 or OR7a deletion and ORF8 termination codon mutation with time lowering pathogenicity.

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The 249RWMD spike protein insertion in Omicron BQ.1 subvariant compensates the 24LPP and 69HV deletions and may cause severe disease than BF.7 and XBB.1 subvariants

Cited by 8 publications

References 44 publications

Highly infectious, less pathogenic and antibody resistant Omicron XBB.1, XBB.1.5 and XBB.1.5.1-XBB.1.5.39 subvariant Coronaviruses do not produce ORF8 protein due to 8th codon GGA=TGA Termination Codon Mutation

Highly infectious, less pathogenic and antibody resistant Omicron XBB.1, XBB.1.5 and XBB.1.5.1-XBB.1.5.39 subvariant Coronaviruses do not produce ORF8 protein due to 8th codon GGA=TGA Termination Codon Mutation

Rapid screening methods for universal binding peptide aptamers against SARS-CoV-2 variant spikes, including omicron variants, and their application to diagnostic and therapeutic agents.

Higher Omicron JN.1 Coronavirus Transmission due to Unique 17MPLF Spike Insertion compensating 24LPP, 69HV, 145Y, 211N and 483V deletions in the spike

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