Difference between revisions of "deLemus"

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===F486P/I ===
 
===F486P/I ===
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<big>The next mutation is F486P/I. Mutation from Phenylalanine (F) to Proline (P) at site 486 shows up in the recent accelerated variant, XBB.1.5, which is currently showing substantial growth in the US.<ref name="CNBC XBB.1.5"/> This mutation renders higher hACE2-binding affinity compared to its ancestor (XBB.1), that is likely responsible for its high growth.<ref name="XBB.1.5"/> We also noticed another leading mutation on the same site, F486I, which could be a dangerous mutation in the coming time.<br /></big>
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<big>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.<ref name="XBB.1.5" /> 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.<ref name="CNBC XBB.1.5" /> Additionally, we have noticed another leading mutation located at the same site, F486I, which may also alter the viral fitness of SARS-CoV-2.<br /></big>
  
  

Revision as of 00:03, 23 January 2023

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 (30/12/2022)

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 figure below summarizes the RBD 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.


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).

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.[4] 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.[5] 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.[6] 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,[5][7][8] allowing them to become dominant in the US and the UK.[9][10] 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.[11][12] 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.[13][14] 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.[15]

Recent emerging variant (EV) data retrieved from GISAID, as of 10 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.[15] The identified leading mutations are listed as follows:

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.[16] 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.[15] Additionally, we have noticed another leading mutation located at the same site, F486I, which may also alter the viral fitness of SARS-CoV-2.


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

R346S/I

R346S, a potential mutation predicted by deLemus, was shown to be involved in the immune escape from the monoclonal antibody S309, a precursor of sotrovimab, in an in vitro experiment. This mutation locates on the epitope of the antibody. After treating the infected cells with S309, R346S (together with P337L) showed up in the spike protein of the virus, substantially lowering its affinity to the antibody without affecting its binding to ACE2.[17].

N450D

N450D, the possible effects of which were not well studied in previous research, is a new potential mutation found by deLemus. This site was located at the β-sheet 1 (N450-F456) region, which was shown to be involved in the reinforcement of the binding between the spike protein and ACE2 in silico.[18].

V445A

V445A is another potential mutation worthy of attention since this site is located at the epitope of several antibodies[19]. This mutation has been shown to negatively impact the neutralization activity of antibody LY-CoV1404 (bebtelovimab) that is highly potent against most VoCs, including the recent omicron variants BA.1.1.59 and BA.2 [20]. In addition, there is also a loss of binding to the spike and reduced ACE2 competition resulted from this mutation [20].

E484R/S

For E484R/S, mutation at E484 has been found to strongly affect the binding and neutralization ability of antibodies, making E484 a site of utmost significance in RBD that could harbor escape mutations (). In fact, E484K and E484Q have been reported in previous VoCs, as well as E484A in the recent omicron lineages of which BA.1.1.159 has been shown to have reduced or completely lost efficacy against several monoclonal antibodies [21].


References

  1. ↑ Jackson, C. B., Farzan, M., Chen, B., & Choe, H. (2021). Mechanisms of SARS-CoV-2 entry into cells. Nature Reviews Molecular Cell Biology, 23(1), 3–20. https://doi.org/10.1038/s41580-021-00418-x
  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. ↑ 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).
  5. ↑ 5.0 5.1 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).
  6. ↑ Yamasoba, D. et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. Cell 185, 2103-2115.e19 (2022).
  7. ↑ Cao, Y., Yisimayi, A., Jian, F., Song, W., Xiao, T., Wang, L., Du, S., Wang, J., Li, Q., Chen, X., Yu, Y., Wang, P., Zhang, Z., Liu, P., An, R., Hao, X., Wang, Y., Wang, J., Feng, R., … Xie, X. S. (2022). Ba.2.12.1, Ba.4 and BA.5 escape antibodies elicited by Omicron Infection. Nature, 608(7923), 593–602. https://doi.org/10.1038/s41586-022-04980-y
  8. ↑ Wang, Q., Guo, Y., Iketani, S., Nair, M. S., Li, Z., Mohri, H., Wang, M., Yu, J., Bowen, A. D., Chang, J. Y., Shah, J. G., Nguyen, N., Chen, Z., Meyers, K., Yin, M. T., Sobieszczyk, M. E., Sheng, Z., Huang, Y., Liu, L., & Ho, D. D. (2022). Antibody evasion by SARS-COV-2 omicron subvariants BA.2.12.1, Ba.4 and BA.5. Nature, 608(7923), 603–608. https://doi.org/10.1038/s41586-022-05053-w
  9. ↑ Callaway, E. What Omicron’s BA.4 and BA.5 variants mean for the pandemic. Nature 606, 848–849 (2022).
  10. ↑ 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).
  11. ↑ Cao, Y., Song, W., Wang, L., Liu, P., Yue, C., Jian, F., Yu, Y., Yisimayi, A., Wang, P., Wang, Y., Zhu, Q., Deng, J., Fu, W., Yu, L., Zhang, N., Wang, J., Xiao, T., An, R., Wang, J., … Wang, X. (2022). Characterization of the enhanced infectivity and antibody evasion of Omicron Ba.2.75. Cell Host & Microbe, 30(11). https://doi.org/10.1016/j.chom.2022.09.018
  12. ↑ 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).
  13. ↑ 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.
  14. ↑ 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).
  15. ↑ 15.0 15.1 15.2 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).
  16. ↑ Cao, Y., Jian, F., Wang, J., Yu, Y., Song, W., Yisimayi, A., Wang, J., An, R., Chen, X., Zhang, N., Wang, Y., Wang, P., Zhao, L., Sun, H., Yu, L., Yang, S., Niu, X., Xiao, T., Gu, Q., … Xie, X. S. (2022). Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. Nature. https://doi.org/10.1038/s41586-022-05644-7
  17. ↑ Magnus. et al. Targeted Escape of SARS-CoV-2 in Vitro from Monoclonal Antibody S309, the Precursor of Sotrovimab. Front Immunol. 13, 966236 (2022).
  18. ↑ Cong, Y. et al. Anchor-Locker Binding Mechanism of the Coronavirus Spike Protein to Human ACE2: Insights from Computational Analysis. J Chem Inf Model. 61(7), 3529–3542 (2021).
  19. ↑ weisblum 2020, eLife 9:e61312
  20. ↑ 20.0 20.1 Cell Rep. 2022 May 17; 39(7): 110812.
  21. ↑ VanBlargan 2022, Nature Medicine volume 28, pages490–495 (2022)


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