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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. 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 USA since late December 2022.[1] 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.[2] 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

Since the outbreak of COVID-19, the virus has been continously evolving, giving rise to new variants. In the face of increasing public health risk that these variants may cause, these variants have been classified and declared as Variants of Concern (VOC) and Variants of Interest (VOI) by WHO, including alpha(B.1.1.7), beta(B.1.351), gamma(P.1), delta(B.1.617.2). Omicron, the recent VOC designated by WHO after being reported in South Africa in November 2021,[3] is genetically diverse and consisted of many different lineages.[4] Omicron was spreading very quickly to many countries after its first report. Soon after the discovery of BA.1, BA.2 was detected and spread across the globe.[5] In April 2022, BA.4 and BA.5 were monitored by the WHO after being found in multiple countries. They showed a significant increase in growth advantage when compared to BA.2.[4] These two variants became dominant in the UK and the US in June 2022.[6] In the meantime, BA.2.12.1 and BA.2.75 were also spreading in the US and India respectively in May 2022.[7][8] In August 2022, XBB, which is a recombinant of BA.2.10.1 and BA.2.75, was surged up in various countries as well.[9] After that, in October 2022, BQ.1, which is a subvariant of BA.5 starting to prevail in France, was found.[10] BQ.1 quickly spread and become the dominant variant by the end of 2022. In the USA, the subvariant of BQ.1, BQ.1.1, covers 36.3% of the total reported cases in December 2022.[11] The recent data of emerging variant (EV) provided by GISAID (as of 2023/01/10) reveals the top 4 spreading lineages: BA.1.1.22, CH.1.1, XBB.1.5, and BQ.1.1. Among these lineages, XBB.1.5 starts to dominate in the USA with more than 40% sequence coverage by January 2023.[11] The identified leading mutations are listed as follows:

K356T

Among all the detected mutations in spikes protein, this site is worthy of being monitored due to its persistent signal since April 2022. The mutation from Lysin(K) to Threonine(T) at site 356 enables N-X-T sequon, which is crucial for glycosylation, a defense mechanism for the virus to hide from immune surveillance, e.g., antibodies. Moreover, the emerging variant provided by GISAID also reveals that the R356T mutation shows up in the top 5 accelerating variants, the BN.1.4 variant.

F486P/I

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.[11] This mutation renders higher hACE2-binding affinity compared to its ancestor (XBB.1), that is likely responsible for its high growth.[2] We also noticed another leading mutation on the same site, F486I, which could be a dangerous mutation in the coming time.


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.[12].

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.[13].

V445A

V445A is another potential mutation worthy of attention since this site is located at the epitope of several antibodies[14]. 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 [15]. In addition, there is also a loss of binding to the spike and reduced ACE2 competition resulted from this mutation [15].

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 [16].


References

  1. ↑ COVID Data Tracker: Variant Proportion https://covid.cdc.gov/covid-data-tracker/#variant-proportions (2023).
  2. ↑ 2.0 2.1 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).
  3. ↑ 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).
  4. ↑ 4.0 4.1 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).
  5. ↑ Yamasoba, D. et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. Cell 185, 2103-2115.e19 (2022).
  6. ↑ Callaway, E. What Omicron’s BA.4 and BA.5 variants mean for the pandemic. Nature 606, 848–849 (2022).
  7. ↑ 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).
  8. ↑ 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).
  9. ↑ 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.
  10. ↑ 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).
  11. ↑ 11.0 11.1 11.2 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).
  12. ↑ Magnus. et al. Targeted Escape of SARS-CoV-2 in Vitro from Monoclonal Antibody S309, the Precursor of Sotrovimab. Front Immunol. 13, 966236 (2022).
  13. ↑ 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).
  14. ↑ weisblum 2020, eLife 9:e61312
  15. ↑ 15.0 15.1 Cell Rep. 2022 May 17; 39(7): 110812.
  16. ↑ VanBlargan 2022, Nature Medicine volume 28, pages490–495 (2022)


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