The prevalence of the 2019 novel coronavirus (SARS-Cov-2, formerly known as 2019-nCoV) that first appeared in Wuhan, China, in December 2019, has rapidly increased. At present, the cases of novel coronavirus pneumonia (COVID-19) caused by 2019-nCoV have been found in many countries around the world. According to the latest data, as of May 15, 2020, there were 4.44 million confirmed cases worldwide, with a cumulative death of more than 300,000. On January 31, 2020, the World Health Organization (WHO) announced 2019-nCoV as a public health emergency of international concern, which means that it may pose risks to multiple countries and require a coordinated international response. This is not the first serious respiratory disease outbreak caused by coronavirus. In the past 20 years, coronavirus has caused three epidemic of infectious diseases including COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS).
1. Coronaviruses
Coronaviruses (CoVs) belong to the order of nested viruses, Coronaviridae. All viruses in the nested virus order have envelopes and contain very large RNA virus genomes, of which coronaviruses have the largest RNA genome of approximately 30 kb. The 3D structure of the coronavirus obtained by cryo-electron tomography shows that it is obviously spherical and has an envelope diameter of about 85nm. A stick-shaped spike can be seen on the surface of the coronavirus, which is also the cause of its name. Coronavirus genomes and subgenomes contain at least 6 open reading frames (ORF), and generally have 5 'cap (leader) and 3' ends (ends) sequence. 5 'cap open reading frame encoding produces a variety of non-structural proteins, non-structural proteins which are involved in the transcription and replication of viruses; coronaviruses have at least four major structural proteins, including spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins. The 3 'ORF of the genome encodes coronavirus proteins, which are essential for virus-cell receptor binding; they are all necessary to produce structurally complete virus particles.
Coronavirus is one of the main viral pathogens that cause respiratory infections. Coronaviruses can be divided into four categories according to genetic and antigen standards, namely α, β, γ and δ coronaviruses. It can cause multi-system infections in a variety of animals. Alpha-Coronavirus and Beta-Coronavirus only infect mammals, usually causing human respiratory diseases and animal gastroenteritis. Livestock such as porcine are susceptible to swine infectious gastroenteritis virus (porcine transmissible gastroenteritis virus), porcine enteric diarrhoea virus (PEDV), swine acute diarrhoea syndrome coronavirus (SADS-CoV) and other α and β coronavirus. γ-Coronavirus and δ-Coronavirus can infect birds, but some of them can also infect mammals. Past studies have identified 6 coronaviruses that may cause human diseases, including 2 highly pathogenic viruses SARS-CoV and MERS-CoV that cause severe respiratory syndrome in humans, and 4 other human coronaviruses, HCoV -NL63 (human coronavirus NL63), HCoV-229E (human coronavirus 229E), HCoV-OC43 (human coronavirus OC43) and HCoV-HKU1 (human coronavirus HKU1), which only cause mild respiratory diseases. The latest research shows that the 2019-nCoV has been isolated from the airway epithelial cells of patients with viral pneumonia in Wuhan. Compared with known coronaviruses that can infect humans, the structure of SARS-CoV-2 is somewhat different, and therefore defined as the seventh coronavirus.

2. The overview of coronavirus infection mechanism and epidemiology
Coronavirus can cause respiratory and intestinal infections in animals and humans. The emergence of 2019-nCoV marks the third epidemic of highly pathogenic coronavirus in recent years. The two high-transmissive and pathogenic diseases caused by coronaviruses before, SARS-CoV and MERS-CoV, have become serious respiratory epidemics worldwide.
In 2002, SARS-CoV spread to 37 countries, causing 8,422 infections and 919 deaths. In 2012, MERS-CoV spread to 27 countries and infected 2,494 people. The disease progression of SARS and MERS is very similar, but the mortality of MERS reached 35%, much higher than that of SARS of about 10%. Symptoms caused by the two viruses usually manifest as moderate to severe respiratory syndrome, and the patients usually develop into severe pneumonia. SARS-CoV uses angiotensin-converting enzyme 2 (ACE2) as the receptor (SARS ACE2 receptors) mainly infecting ciliary bronchial epithelial cells and type II alveolar cells, while MERS-CoV uses dipeptidyl peptidase 4, DPP4) as the receptor, mainly infecting undifferentiated bronchial epithelial cells and type II alveolar cells.
Both SARS-CoV and MERS-CoV are zoonotic pathogens, and they are transmitted to humans by crossing species barriers. SARS coronavirus was first discovered in the live animal market in Shenzhen, China, where it was found in civet cats and other animals. Subsequent studies have shown that civet cats are only intermediate hosts. Similarly, the dromedary is only the intermediate host of MERS-CoV. The final study found that there are genetically diverse coronaviruses associated with SARS-CoV and MERS-CoV in bats, indicating that bats are likely to be the main natural reservoirs for α-coronavirus and β-coronavirus. According to the current viral gene sequence data, all human coronaviruses come from animals: SARS-CoV, MERS-CoV, HCoV-NL63 and HCoV-229E originate from bats; HCoV-OC43 and HCoV-HKU1 may be derived from rodents. Livestock played the role as an intermediate host, enabling viruses to spread from natural hosts to humans.
2019-nCoV and SARS-CoV have many similarities in the population and clinical characteristics. Most patients with 2019-nCoV infection have high fever, and some patients show symptoms of breathlessness. Chest X-rays show that the lungs of the patient are infiltrating lesions. The 2019-nCoV gene sequencing results are less similar to SARS-CoV (about 79%), more different from MERS-CoV (about 50%), and to the two bat-derived coronaviruses bat-SL-CoVZC45 and bat -SL-CoVZXC21 is relatively similar (88%). Pairwise protein sequence analysis of 7 conserved non-structural proteins indicates that the virus belongs to the bat SARS-CoV species, further proving that 2019-nCoV originated from bats. Importantly, homology modeling shows that the binding domain of 2019-nCoV and ACE2 receptor is structurally similar to SARS-CoV. Although there are amino acid mutations in its receptor binding domain, several key amino acids have changed. But after the change, the amino acids perfectly maintain the stability of the structural conformation between the viral S-protein and the ACE2 receptor, which initially reveals that ACE2 is its receptor for entering cells.
Since SARS-CoV-2 can be transmitted from person to person, the outbreak of the virus is mainly caused by the spread and transfer of people. The most likely way of virus transmission is through the individual's respiratory tract. The Weibull distribution shows that the incubation period for 2019-nCoV is 2.1 to 11.1 days, within a 95% confidence interval, and the average incubation period is estimated to be 6.4 days. The latest results published on February 6 show that the median incubation period for 2019-nCoV is 3.0 days, and the start and end of the incubation period is 0 to 24 days.
3. The research strategy and discovery of coronavirus drug
There are no special drugs specifically for the prevention and treatment of coronavirus. There is no 2019-nCoV vaccine or specific antiviral drugs during the virus outbreak, and non-specific therapeutic interventions are usually used to prevent serious complications and reduce severe morbidity and mortality, such as providing supportive care, including adequate rest, providing fluids analgesics. Meanwhile, Chinese medicine, hormone drugs, broad-spectrum antibiotics, antiviral drugs, antifungal drugs and interferon-α2b can be used to minimize the risk of co-infection of pathogens. Although coronaviruses have a high species diversity, they share key genomic elements, which is crucial for target design for new drug development. The viral genome information and bioinformatics characteristics guide the idea of discovering potential drugs and looking for new discoveries from past drugs.
To be continued in Part II…

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