ACE2 is one of the hottest target of SARS-CoV-2 Invasion

Date:   4/28/2020 3:34:33 AM ( 4 y ago)

On February 11, 2020, the novel coronavirus that raged for more than one month in China was officially named SARS-CoV-2 by the International Virus Classification Committee. From the nomenclature, it is not difficult to find that SARS-CoV-2 and SARS coronavirus, which were frightening 17 years ago, do have a deep origin: they are both coronaviruses and highly pathogenic. What exactly is this coronavirus? The so-called coronavirus refers to a group of viruses. It is named after a circle of nail-like protrusions (thorn protein) on the surface of the virus particles, which looks like a crown. Coronaviruses are important pathogens in humans and vertebrates. Before the outbreak of COVID-19, there were six known human coronaviruses, called coronaviruses 229E, OC43, HKU1, NL63, SARS, and MERS. The first four can cause the common cold or intestinal diseases, which are weaker than influenza; Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are highly pathogenic coronaviruses, which can cause serious respiratory diseases and even death.

So what is ACE2? What does it have to do with the novel coronavirus?

We know that viruses generally consist of a nucleic acid core and a protein shell. They do not have the ability to replicate autonomously and cannot be self-reliant. So the virus needs to infect the cell (host), and use the host's nucleic acid synthesis system and protein expression system to complete replication and amplification. So how does SARS-CoV-2 invade cells?

On January 21, 2020, researchers at the Shanghai Pasteur Institute used the model analysis of the 2019-nCoV (now SARS-CoV-2) S-protein structure to take the lead in speculating that 2019-nCoV is the same as SARS-CoV, Invade through the mediation of ACE2 receptors on the surface of human cells to infect human respiratory epithelial cells. Later, the Shi Zhengli team of the Wuhan Virus Research Institute published an article in Nature on February 3, confirming that the novel coronavirus and SARS coronavirus use the same cell receptor ACE2. Angiotensin-converting enzyme 2 (ACE2), as the first reported ACE homolog in 2000, became known to the world, and ACE belongs to the renin-angiotensin system ACE functions in reverse, checks and balances each other, and participates in regulating the normal development and steady-state balance of the cardiovascular system.

In addition, ACE2 is also related to virus invasion into cells. Multiple domains of ACE2 protein can be combined with viral spike proteins and can be used as the receptors for two SARS-CoV and HCoV-NL63 coronaviruses. Early studies observed that ACE2 is mainly expressed in the heart, kidney, testis, lung, gastrointestinal tract and other tissues. There are indeed many studies that indicate that new coronary pneumonia can indeed cause damage to the heart, kidneys, and digestive tract, and may cause testicular function damage.

ACE2 protein is mainly distributed in type Ⅱ alveolar cells (AT2 cells) in lung tissue, but also in small amounts in type I alveolar cells (AT1 cells) and tracheal epithelial cells. When coronavirus enters the human body, it first binds to ACE2, causing protein degradation, reducing the amount of ACE2, and imbalance of the renin-angiotensin system, resulting in impaired lung function. The consistency of the tissue expression of ACE2 protein and the clinical observation of patients demonstrates the key role of ACE2 as a receptor in the spread of SARS-CoV-2 virus.

More interestingly, on February 17, scientists from the University of Texas and the National Institutes of Health uploaded their latest research progress on bioRxiv. They used cryo-electron microscopy to analyze the structure of the novel coronavirus S protein. They also analyzed and verified that the S-protein of 2019-nCoV has an ultra-high affinity with the ACE2 receptor (KD = 14.7 nM) by surface plasmon resonance (SPR) SARS-CoV (KD = 325.8 nM) is 10-20 times, this result coincides with the recently announced COVID-19 basic infection index R0 = 3.77, which is higher than the conclusion of SARS. Once again highlights the important role of ACE2 in the spread of new coronary pneumonia. ACE2 plays a huge role in SARS-CoV-2 infection and transmission, which also means that ACE2 is likely to become a key point in the treatment of new coronary pneumonia. At 3 a.m. on February 19, Zhou Qiang Laboratory of West Lake University successfully analyzed the full-length structure of ACE2 using cryo-electron microscopy technology, which further clarified the direction for scientists to break through the ACE2 receptor. In theory, if the binding site of ACE2 and SARS-CoV-2 is blocked by specific antibodies or other substances, it is possible to block the invasion of the virus to the cells, and then achieve the purpose of treatment and prevention.

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