The “Four Kings” of the COVID-19 mutant strain

The global pandemic of the new crown epidemic has caused huge losses and impacts on global economic growth, cultural exchanges and the daily lives of people around the world. Up to now, although the development of the global epidemic has been effectively prevented and controlled. However, with the mutation of the COVID-19, some countries have emerged mutated strains that spread more rapidly. Among them, the new coronavirus variants that have occurred in the United Kingdom, South Africa, Brazil, India, etc. can be described as the “four kings” of the mutant strains.

• Alpha appeared in England in September 2020 and caused a surge in winter cases, bringing the United Kingdom back into lockdown in January. Other countries are close behind, especially in Europe. According to the World Health Organization, it became the dominant strain in the United States in early April, and as of May 25, at least 149 countries had reported this strain.
• Beta appeared in South Africa in August 2020, leading to a comeback of Covid-19 cases, sweeping southern Africa. As of May 25, at least 102 countries have reported this situation.
• Gamma was first discovered in the Amazon city of Manaus in December 2020, causing a surge in cases, straining Brazil’s health system and causing oxygen shortages. As of May 25, at least 59 countries have reported this situation.
• Delta was first discovered in India in October 2020, and as of late May, the virus has been found in at least 54 countries. The British Emergency Science Advisory Group stated on May 13 that its transmission rate may be 50% higher than that of the alpha variant

The 2019-nCoV belongs to the beta genus of coronaviruses. It is a single-stranded positive-stranded RNA virus with an envelope. The particles are round or elliptical and have a diameter of 60-140nm. It has 5 essential genes, which respectively encode 4 structural proteins of Nucleocapsid protein (N), Envelop protein (E), Membrane protein (M) and Spike Glycoprotein (S), and Hemagglutinin-esterasedimer (RdRp). The Nucleocapsid protein (N) wraps the RNA genome to form a stable nucleocapsid. The nucleocapsid is surrounded by a virus envelope (E) for protection. In the virus envelope, there are Membrane protein (M) and Spike Glycoprotein ( S) Equal protein. Among them, the new coronavirus uses the surface spike protein to bind to cell receptors, and then invade cells. Spike Glycoprotein is also an important structure for the immune system to recognize viruses and neutralize them with antibodies. These four new coronavirus mutant strains are precisely because of the mutations in some key sites of the Spike Glycoprotein (S), which leads to significant changes in the affinity of the mutant strains with cell receptors or with neutralizing antibodies. This further led to these four mutant strains becoming the main strains currently circulating.

The main characteristics of Alpha and Beta mutant S proteins are as follows:

The team led by Professor Chen Bing from Harvard Medical School and Boston Children’s Hospital recently published a series of research results in the top academic journal “Science”, showing that it was first discovered in the alpha variant. The amino acid changes A570D and S982A help the spike protein trimer to keep its receptor binding domain in a position where it binds to the receptor. At the same time, N501Y increases the binding affinity of the receptor binding domain to the ACE2 receptor. Researchers speculate that these changes may allow alpha variants to infect cell types that have fewer ACE2 receptors.

The team’s research results also show that in the Beta virus, the S protein largely retains the structure of the G614 trimer and has almost the same biochemical stability. N501Y, K417N and E484K in RBD did not cause major structural changes, but the loss of salt bridges between K417 and ACE2 Asp30 and Glu484 and ACE2 Lys31 alleviated the increase in receptor affinity conferred by N501Y. K417N and E484K may cause antibodies targeting RBD-2 epitope to lose binding and neutralization. The accompanying mutations in NTD reshape the surface of the antigen and greatly reduce the effectiveness of neutralizing antibodies against the NTD-1 epitope. Beta variants are likely to be selected under a certain degree of immune pressure

The main features of Gamma mutant S protein:

In a study published in the journal Science on April 14, 2021, an international team of researchers conducted related research and analysis on the Gamma (P.1) new coronavirus variants that appeared in Brazil. The results show that the Gamma (P.1) virus has 17 unique amino acid changes, 10 of which are present in the spike protein, including the three most worrying variants: N501Y, E484K, and K417T. N501Y and K417T interact with human angiotensin-converting enzyme 2 (ACE2), while E484K is located in the loop area outside the human ACE2 interface. It is worth noting that these three variants also exist in the South African variant (Beta, B.1.351) that has received much attention, and N501Y is present in the British variant (Alpha, B.1.1.7). Because they seem to make the virus variant bind more tightly to human cells, in some cases, to help evade antibodies.

The main features of Delta mutant S protein:

An article published on the bioRxiv platform on June 17, 2021 determined that the P681R mutation is highly conserved in the delta (B.1.617) lineage through the study of delta (B.1.617) variants. Through in-depth research, it was found that the mutation of P681R promoted furin-mediated cleavage of the spike protein and accelerated cell-cell fusion. And to promote the P681 mutation to enhance the virus’s ability to escape neutralizing antibodies.

According to the epidemiological and etiological characteristics of the “four kings” of COVID-19 mutant strain, it can be seen that the local epidemic of the epidemic will be the normal state of the global epidemic. Actively responding to the international epidemic prevention policy and seeking a broad-spectrum and effective new crown vaccine will become our powerful weapon against the epidemic.

(Data source: WHO)