deLemus

From
Revision as of 15:37, 28 January 2023 by Alvin (talk | contribs) (→‎E484R/S)
Jump to navigation Jump to search

Dynamic Expedition of Leading Mutations in SARS-CoV-2 Spike Glycoprotein

Spike Glycoprotein

The spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a trimeric type I viral fusion protein that binds the virus to the angiotensin-converting enzyme 2 (ACE2) receptor of a host cell.[1] It is composed of 2 subunits: the N-terminal subunit 1 (S1) and C-terminal subunit 2 (S2), within which multiple domains lie. The S1 region facilitates ACE2 binding and is made up of an N-terminal domain (NTD ~ 1 – 325), a receptor-binding domain (RBD ~ 326 – 525), and 2 C-terminal subdomains (CTD1 and CTD2 ~ 526 – 688), while the downstream S2 region is responsible for mediating virus-host cell membrane fusion.

Update (27/01/2023)

A recently discovered omicron sublineage known as XBB.1.5 has been spreading rampantly in the US since late December 2022.[2] Even though this new variant harbors only a single novel mutation, F486P, its hACE2-binding affinity has been significantly increased to a level of up to five folds when compared to its ancestor, XBB.1.[3] The figures below summarize the mutations carried by various emerging variants, juxtaposed with our detected leading mutations. As depicted, our method has successfully reported the crucial F486P mutation that defines the XBB.1.5 strain. In fact, our method has outlined this specific mutation since as early as November 2022. The following leading mutations are outlined by deLemus in December 2022:
- H146- in BQ.1.1 (reported by GISAID on 2023.01.25)


Summary

The constantly shifting epidemiology of coronavirus disease 2019 (COVID-19) ever since its initial outbreak has been a result of the continuous evolution of its etiological agent, SARS-CoV-2, from which numerous variants have been generated. Even within the first 2 years of this pandemic, the World Health Organization (WHO) has already announced 4 variants of concern (VOC), which are the previously circulating alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2) strains, and many other variants of interest (VOI). As new variants emerge, more mutations show up, improving the fitness of the virus. For example, N501Y (in B.1.1.7), E484Q and L452R (in B.1.617) can increase the binding affinity between the spike protein and ACE2.[4]

The latest SARS-CoV-2 lineage to be designated the status of VOC would be omicron (B.1.1.529) which first originated from South Africa.[5] This particular lineage alone has undergone substantial evolution over the course of its global dominance, spreading across the world like wildfire while simultaneously producing a diverse soup of dissimilar subvariants.[6] The first of its kind would be the BA.1 strain first appeared in November 2022. The supremacy of BA.1, however, would not last long, forasmuch as the emergence of the more fit BA.2 strain in December 2022 would eventually outcompete its antecedent.[7] Few months later, between March and May 2022, the successive emergences of BA.2.12.1, BA.4 and BA.5, and BA.2.75 would once again garnered the attention of the WHO and multiple countries. For one, the BA.2.12.1, BA.4, and BA.5 subvariants were found to possess enhanced antibody evasion and transmissibility when compared to the formerly active BA.2 strain,[6][8][9] allowing them to become dominant in the US and the UK.[10][11] BA.2.75, on the other hand, was the dominant variant in India, which habors higher hACE2-binding affinity than the BA.4 and BA.5 subvariants.[12][13] The complex interactions between these omicron sublineages prompted the creations of even more novel strains, including the recombinant XBB subvariant derived from BA.2.10.1 and BA.2.75 in August 2022, and the BQ.1 subvariant derived from BA.5 in October 2022. Like their predecessors, XBB swiftly rose to prominence upon its emergence, which was then succeeded by BQ.1 up till the end of 2022.[14][15] In fact, BQ.1.1, a descendent of BQ.1, was found to be the culprit behind 36.3% of the total US reported COVID-19 cases in December 2022.[16]

Recent emerging variant (EV) data retrieved from GISAID, as of 17 January 2023, has revealed that the top 4 most rapidly spreading lineages are the BA.1.1.22, CH.1.1, XBB.1.5, and BQ.1.1 variants, among which XBB.1.5 has been found to be especially prevalent in the US, making up of more than 40% of its sequence coverage in early January 2023.[16] The identified leading mutations are listed as follows:

NTD

CTDs

S2

K356T

Amino acid site 356, which corresponds to the K356T mutation, initially piqued our interest due to its persistent mutational signal since April 2022, based on our deLemus analysis. The importance of this mutation would subsequently be affirmed, as it is carried by one of the top accelerating variants, BN.1.4, according to the EV data retrieved from GISAID. In fact, a recent study has revealed that this particular mutation promotes immune evasion.[17] Moreover, it has come to our attention that this lysine-to-threonine mutation gives rise to an NXT sequon (354NRT356), which may potentially enable the generation of a novel N-glycosylation site.

F486P/I

Amino acid site 486 has been exhibiting a strong mutational signal since November 2022, based on our deLemus analysis. Mutation at this site in the form of F486P is carried by the currently proliferating XBB.1.5 variant, rendering this variant with an enhanced hACE2-binding affinity when compared to its ancestor, XBB.1.[3] It is likely that the tighter receptor attachment confers quicker transmissibility for the XBB.1.5 strain, as demonstrated by its looming dominance in the US.[16] Additionally, we have noticed another leading mutation located at the same site, F486I, which may also alter the viral fitness of SARS-CoV-2.

E583D

Amino acid site 583, which corresponds to the E583D mutation, has been outlined to bear a strong mutational signal since December 2022, based on our deLemus analysis. This CTD mutation has emerged in one of the top accelerating variants, BQ.1.1. The glutamic acid-to-aspartic acid substitution allows the site to retain its negative charge, and further investigations would be required to confirm the possible viral functions this mutation may confer.

Q613H

Amino acid site 613, corresponding to the Q613H mutation, has been detected to be mutationally active since December 2022, based on our deLemus analysis. This particular mutation is currently harbored by one of the top accelerating variants, BQ.1.1. While current studies have yet to elucidate its potential functions, its close proximity to the crucial D614G mutation carried by all existing variants has led researchers to speculate that it may pose similar effects in enhancing the replicative fitness and transmissibility of SARS-CoV-2.[18][19]



The following leading mutations call for special attention with respect to the upcoming variants.

R346I/S

The R346I/S mutation outlined by our deLemus analysis is located at an RBD epitome to which multiple class 3 antibodies bind.[20] Structural analyses have revealed that this arginine-to-isoleucine/serine change weakens the intermolecular interactions between amino acid 346 and several class 3 antibodies, enabling virions bearing this mutation to possess enhanced immune evasion capabilities.[21] In fact, experimental studies have demonstrated that R346S in particular can promote neutralization resistance of viruses without comprising their ACE2-binding affinity.[22][23]

N450D

The N450D mutation outlined by our deLemus analysis is located at the RBD β-sheet 1 region which has been shown to reinforce the spike-ACE2 binding in silico.[24] The possible effects of this mutation have yet to be studied, but it has been speculated that the substitution of an electrically neutral asparagine residue to an anionic aspartic acid residue may disfavor the virus-receptor attachment process, owing to the overall negative charge of the ACE2 binding surface.[25]

V445A

The V445A mutation outlined by our deLemus analysis is located at an RBD epitope targeted by several antibodies.[26] This mutation has been experimentally shown to not only diminish the neutralization activity of the antibody LY-CoV1404 (bebtelovimab) that is highly potent against most VOCs, including the previously circulating omicron subvariants BA.1.1.59 and BA.2, but also reduce ACE2 competition.[27]

E484R/S

The E484R/S mutation outlined by our deLemus method is located within the receptor binding motif (RBM) of the RBD. Recognized by ACE2 and multiple neutralizing antibodies,[28] immense selection pressure exerted on this amino acid site has generated a high degree of polymorphism for residue 484, as seen from the fact that most SARS-CoV-2 variants carry substitutions in this site, encompassing the E484K of beta, gamma, and eta (B.1.525), E484Q of kappa (B.1.617.1), and E484A  of omicron. All these mutations confer immune escape effects,[18][29][30] where the 2 former ones in particular can additionally strengthen the ACE2-binding affinity of the virus.[28] Similarly, E484R, which also replaces the initially anionic aspartic acid residue with a cationic one, has been shown to promote both immune evasion and ACE2-binding.[28] The function of E484S, on the other hand, have yet to be deduced.

D574V

The D574V mutation outlined by our deLemus analysis is located at the CTD1 region. Since the aspartic acid residue of amino acid site 574 is capable of interacting with the pH-dependent S2 refolding domain responsible for regulating RBD up-down motion, its substitution to an electrically neutral valine residue may alter the endosomal entry efficiency and immune evasion ability of SARS-CoV-2.[31]

P681Y

The P681Y mutation outlined by our deLemus analysis is located at the C-terminal of the CTD2, which contains the S1/S2 furin cleavage site (681PRRAR↓S686) important for viral transmission.[32][33] This amino acid site is particularly polymorphic, as demonstrated by the fact that multiple existing variants carry divergent mutations at this site, being the P681H of alpha and omicron and P681R of delta and kappa. Interestingly, this substitution is speculated to diminish the cleavage efficiency of the S1/S2 interface because the bulky nature of tyrosine hinders the binding of furin to the cleavage loop.[34][35]

K147-

K147- is a potential mutation detected by deLemus. Previous studies in molecular dynamics have shown that the K147 position is involved in the interaction between the NTD and multiple monoclonal antibodies (mAbs).[36] Also, there was evidence that another type of mutation at the same position (K147T) can impair immune therapy.[37] A deletion at this position may affect the antigen-antibody interaction, providing an immune escape to the virus.

A262S

A262S is a potential mutation in the NTD detected by deLemus. It was shown that this mutation can enhance the utilization of ACE2 in various mammals, including dogs and cats, which indicates that variants carrying this mutation might be able to spread among pets.[38] Also, A262S was found to exhibit in the viruses isolated from minks.[39]

T323I

T323 is an O-glycosylation site, whose glycan, after removal, will affect the binding between the spike protein and ACE2 or antibody.[40] There is also evidence that the glycosylation of this site is highly related to the maintenance of the RBD as a monomer.[41] The mutation T323I might remove this O-glycosylation site.

References

  1. ↑ Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 23, 3–20 (2021).
  2. ↑ COVID Data Tracker: Variant Proportion https://covid.cdc.gov/covid-data-tracker/#variant-proportions (2023).
  3. ↑ 3.0 3.1 Yue, C. et al. Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion. bioRxiv https://www.biorxiv.org/content/10.1101/2023.01.03.522427v1 (2023).
  4. ↑ Aggarwal, A. et al. Mechanistic Insights into the Effects of Key Mutations on SARS-CoV-2 RBD–ACE2 Binding. Phys Chem Chem Phys 23, 26451–26458 (2021)
  5. ↑ Karim, S. S. A. & Karim, Q. A. Omicron SARS-CoV-2 variant: a new chapter in the COVID-19 pandemic. Lancet 398, 2126–2128 (2021).
  6. ↑ 6.0 6.1 Tegally, H. et al. Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa. Nat. Med. 28, 1785–1790 (2022).
  7. ↑ Yamasoba, D. et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. Cell 185, 2103-2115.e19 (2022).
  8. ↑ Cao, Y. et al. BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron Infection. Nature 608, 593–602 (2022).
  9. ↑ Wang, Q. et al. Antibody evasion by SARS-CoV-2 omicron subvariants BA.2.12.1, BA.4 and BA.5. Nature 608, 603–608 (2022).
  10. ↑ Callaway, E. What Omicron’s BA.4 and BA.5 variants mean for the pandemic. Nature 606, 848–849 (2022).
  11. ↑ Del Rio, C. & Malani, P. N. COVID-19 in 2022 - The Beginning of the End or the End of the Beginning? JAMA - J. Am. Med. Assoc. 327, 2389–2390 (2022).
  12. ↑ Cao, Y. et al. Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75. Cell Host Microbe 30, (2022).
  13. ↑ Shaheen, N. et al. Could the New BA.2.75 Sub-Variant Cause the Emergence of a Global Epidemic of COVID-19? A Scoping Review. Infect. Drug Resist. 15, 6317–6330 (2022).
  14. ↑ Wang, Q. et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell 1–8 (2022) doi:10.1016/j.cell.2022.12.018.
  15. ↑ European Centre for Disease Prevention and Control: Spread of the SARS-CoV-2 Omicron variant sub-lineage BQ.1 in the EU/EEA https://www.ecdc.europa.eu/sites/default/files/documents/Epi-update-BQ1.pdf (2022).
  16. ↑ 16.0 16.1 16.2 Highly immune evasive omicron XBB.1.5 variant is quickly becoming dominant in U.S. as it doubles weekly https://www.cnbc.com/2022/12/30/covid-news-omicron-xbbpoint1point5-is-highly-immune-evasive-and-binds-better-to-cells.html (2023).
  17. ↑ Cao, Y. et al. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. Nature (2022). doi:10.1038/s41586-022-05644-7
  18. ↑ 18.0 18.1 Harvey, W. T. et al. SARS-CoV-2 variants, Spike mutations and immune escape. Nat Rev Microbiol 19, 409–424 (2021).
  19. ↑ Bugembe, D. L. et al. Emergence and spread of a SARS-COV-2 lineage a variant (A.23.1) with altered Spike Protein in Uganda. Nat Microbiol 6, 1094–1101 (2021).
  20. ↑ Gaebler, C. et al. Evolution of antibody immunity to SARS-CoV-2. Nature 591, 639–644 (2021).
  21. ↑ Wang, Q. et al. Resistance of SARS-CoV-2 omicron subvariant BA.4.6 to antibody neutralisation. Lancet Infect Dis 22, 1666–1668 (2022).
  22. ↑ Yi, C. et al. Comprehensive mapping of binding hot spots of SARS-CoV-2 RBD-specific neutralizing antibodies for tracking immune escape variants. Genome Med 13, (2021).
  23. ↑ Magnus, C. L. et al. Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab. Front Immunol 13, (2022).
  24. ↑ Cong, Y. et al. Anchor-locker binding mechanism of the coronavirus spike protein to human ACE2: Insights from computational analysis. J Chemical Inf Model 61, 3529–3542 (2021).
  25. ↑ Xie, Y. et al. Spike proteins of SARS-CoV and SARS-CoV-2 utilize different mechanisms to bind with human ACE2. Front Mol Biosci 7, (2020).
  26. ↑ Weisblum, Y. et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. eLife 9, (2020).
  27. ↑ Westendorf, K. et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Cell Rep 39, 110812 (2022).
  28. ↑ 28.0 28.1 28.2 Gan, H. H., Twaddle, A., Marchand, B. & Gunsalus, K. C. Structural modeling of the SARS-CoV-2 spike/human ACE2 complex interface can identify high-affinity variants associated with increased transmissibility. J Mol Biol 433, 167051 (2021).
  29. ↑ Liu, Z. et al. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Cell Host Microbe 29, (2021).
  30. ↑ VanBlargan, L. A. et al. An infectious SARS-CoV-2 B.1.1.529 omicron virus escapes neutralization by therapeutic monoclonal antibodies. Nat Med 28, 490–495 (2022).
  31. ↑ Zhou, T. et al. Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains. Cell Host Microbe 28, (2020).
  32. ↑ Jaimes, J. A., Millet, J. K. & Whittaker, G. R. Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1/S2 Site. iScience 23, 101212 (2020).
  33. ↑ Hoffmann, M., Kleine-Weber, H. & Pöhlmann, S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol Cell 78, (2020).
  34. ↑ Henrich, S. et al. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Mol Biol 10, 520–526 (2003).
  35. ↑ Tian, S. A 20 residues motif delineates the furin cleavage site and its physical properties may influence viral fusion. Biochem Insights 2, (2009).
  36. ↑ Zhou, L, et al. Predicting Spike Protein NTD Mutations of SARS-CoV-2 Causing Immune Evasion by Molecular Dynamics Simulations. Phys Chem Chem Phys 24, 3410–3419 (2022).
  37. ↑ McCallum, M. et al. N-Terminal Domain Antigenic Mapping Reveals a Site of Vulnerability for SARS-CoV-2. Cell 184, 2332-2347 (2021).
  38. ↑ Wang, Q et al. Key Mutations on Spike Protein Altering ACE2 Receptor Utilization and Potentially Expanding Host Range of Emerging SARS‐CoV‐2 Variants. J Med Virol. 95, 1-11 (2022).
  39. ↑ Ahmed E. et al. Mutational Spectra of SARS-CoV-2 Isolated from Animals. PeerJ 8 (2020).
  40. ↑ Gstöttner, C. et al. Structural and Functional Characterization of SARS-CoV-2 RBD Domains Produced in Mammalian Cells. Anal Chem 93, 6839–6847 (2021)
  41. ↑ Klausberger, M. et al. Designed SARS‐CoV‐2 Receptor Binding Domain Variants Form Stable Monomers. Biotechnol J 17, 2100422 (2022)


Map

Retrieved from "https://wiki.laviebay.hkust.edu.hk/deLemus/index.php?title=deLemus&oldid=1321"