deLemus
Dynamic Expedition of Leading Mutations in SARS-CoV-2 Spike Glycoprotein
Spike Glycoprotein
The spike glycoprotein is a trimeric type I viral fusion protein that binds the virus to the angiotensin-converting enzyme 2 (ACE2) receptor on a host cell.
The spike glycoprotein per se 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: N-terminal domain (NTD ~ 1 – 325 ), 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)
Summary
Since the outbreak of COVID-19, there have been new variants emerging. In the first 2 years of the pandemic, WHO has announced 4 Variant of Concern (VOC) so far, namely alpha(B.1.1.7), beta(B.1.351), gamma(P.1), delta(B.1.617.2). Omicron, the latest lineage designated as a VOC by the WHO after being reported in South Africa in November 2021,[1] has various subvariants, including BA.1 (the first subvariant of omicron), BA.2,[2] BA.4, and BA.5.[3] 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.[4] In April 2022, BA.4 and BA.5 were monitored by the WHO after being found in multiple countries, and they showed a significant increase in growth advantage when compared to BA.2.[3] These two variants became dominant in the UK and the US in June 2022.[5] In the meantime, BA.2.12.1 and BA.2.75 were also spreading in the US and India respectively in May 2022.[6][7] In August 2022, XBB, which is a recombinant of BA.2.10.1 and BA.2.75, was found to have a small outbreak in various countries such as Singapore.[8] After that, in October 2022, BQ.1, which is a subvariant of BA.5 starting to prevail in France, was found.[9] deLemus can highlight the leading mutation in spikes glycoprotein of SARS-CoV-2. The leading mutations of deLemus not only capture the mutation signal from reported variants but also other mutations that potentially show up in the next variant.
K356T
Among all the detected mutations in spikes protein, this site is worthy to be 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.[10] This mutation renders higher hACE2-binding affinity compared to its ancestor (XBB.1), that is likely responsible for its high growth.[11] We also noticed another leading mutation on the same site, F486I, which could be a dangerous mutation in the coming time.
Other than confirmed mutation as described above, deLemus also highlight several leading mutations in spike glycoprotein. These mutations haven't been mentioned or reported in the circulating variant which is worth to be monitored further.
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]
V445A
TEMP
N450D
TEMP
E484R/S
TEMP
References
- ↑ 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).
- ↑ Arora, P. et al. Comparable neutralisation evasion of SARS-CoV-2 omicron subvariants BA.1, BA.2, and BA.3. Lancet Infect. Dis. 22, 766–767 (2022).
- ↑ 3.0 3.1 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).
- ↑ Yamasoba, D. et al. Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike. Cell 185, 2103-2115.e19 (2022).
- ↑ Callaway, E. What Omicron’s BA.4 and BA.5 variants mean for the pandemic. Nature 606, 848–849 (2022).
- ↑ 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).
- ↑ 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).
- ↑ 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.
- ↑ 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).
- ↑ 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).
- ↑ 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).
- ↑ Magnus. et al. Targeted Escape of SARS-CoV-2 in Vitro from Monoclonal Antibody S309, the Precursor of Sotrovimab. Front Immunol. 13, 966236 (2022).
