Advanced Biochemistry

Snow Du

What are the themes?

This project is regarding COVID-19 pandemic which later was known to be caused by SARS-CoV-2. It’s more fun or in other words, strange project since we are still living in this ongoing pandemic and being affected by this virus. Wearing masks, virtual events, and classes, no large gathering has become a new normal for over a year. Numorous people have lost their family to this virus, countless jobs have vaporized from the market due to the closure of the cities or even the whole county led to historically high employment rate. Here, I have gathered the information regarding SARS-CoV-2 and organized them in the following themes:

Clinical Features of Mystery Pneumonia

SARS-CoV-2 is believed to be originated from Wuhan, Hubei Province in December 2019 with multiple unknown caused pneumonia patients got admitted to the hospital1. In January, epidemiology and clinical characterization of the patients who were infected with pneumonia have been determined. It has also been found that this disease had similar clinical features as the Middle East Respiratory Syndrom (MERS) which then was suspected that this disease could be caused by a coronavirus and started to call this disease 2019-nCoV. Though this chapter would not be focusing on biochemistry, the discovery of SARS-CoV-2 was still the starting point of revealing SARS-CoV-2.

Determination of Causative Agent

As the disease threatened human lives nationally and globally, it’s expected that after discovering this fatal and extremely contagious novel coronavirus there would be an urgent need to identify and characterize this novel coronavirus, especially due to the horrible memory from the coronavirus-related pandemics that have been taken place in 2003 (SARS) and 2013 (MERS). Hence, started with China where the virus was thought to be originated, many microbiological studies have been rapidly done and shared with the world including genomic information and crystal structure for this novel coronavirus.

Major Scientific Innovations
Feb 2020 – 2019-nCoV was successfully isolated from human airway epithelial cells via transmission electron microscopy. The viral RNA was then extracted and sequenced. By multiple sequence alignment, this novel coronavirus was identified as SARS-like coronaviruses within the subgenus sarbecovirus. 2019-nCoV was then considered as the most likely causative agent of this mystery pneumonia3.

Cell Entry and Structural Basis of SARS-CoV-2

Again, as the number of infection cases exponentially increasing every single day, the urge to develop novel treatments grew even more. Same as many other viruses, cell entry is one of the most essential steps in order to infect human beings, thus the cell entry mechanism has been seen as the major target for effective treatment. Spike protein of SARS-CoV-2 has been determined as the crucial transmembrane trimeric glycoprotein that’s embedded in the envelope of SARS-CoV-2. By studying the structure of SARS-CoV-2 and the mechanism of it to enter the cell, antigenic characters were determined and they are beneficial for virus detection and development of vaccines and anti-viral therapeutics. Understanding SARS-CoV-2 at a molecular level has brought more light of hope to humans to defeat this virus.

Major Scientific Innovations
Mar 2020 – Led by Jason McLellan and his team, the crystal structure of 2019-nCoV Spike at its prefusion conformation was determined using cryo-electron microscopy (cryo-EM)4.
Mar 2020 – Led by Xinquan Wang and his team in China, the crystal structure of SARS-CoV-2 Spike receptor-binding domain (RBD), when bound to human ACE2 receptor, was determined using cryo-EM5.
April 2020 – Despite ACE2, Stefan Pöhlmann and his team have proved a serine protease, TMPRSS2 to be involved in the cell entry mechanism of SAR-CoV-2 based on the previous knowledge of SARS-CoV-1 and MERS-CoV and can be blocked by serine protease inhibitor6.
Nov 2020 – A virus-host factor, neuropilin-1, has been determined to play an essential role in cell entry mechanism where it would have to bind to a furin cleavage site in order for the protease to cleave the S1 subunit. Interestingly, this host factor was not found in SARS-CoV-1 which can be seen as a potential target for future antiviral therapeutics7.

Immune Responses for SARS-CoV-2

With an enormous number of infection cases globally, ICU systems around the world have been experiencing a non-precedent shortage due to an unexpectedly huge number of severe cases with multiple organ failures. Many symptoms are known to be caused by inflammation in the organs induced by immune responses. It’s a great way to tie the understandings from the molecular level of SARS-CoV-2 with cellular level or even organ systems. Understanding the immune system responses to SARS-CoV-2 would provide an insight into vaccine development.

Major Scientific Innovations
June 2020 – Ai-Long Huang and his team has discovered the antibody responses to SARS-CoV-2 which provided as great potential for detecting infection cases8.
March 2020 – Kritas Spyridon along with his team defined the pro-inflammatory pathway that has causes many severe clinical symptoms9.
June 2020 – SARS-CoV-2 induced immune responses at a cellular level have been defined by measuring the immune T cells, CD4+, CD8+ production in the responses to SARS-CoV-210.

Genetic Factors Involving in Transmission of SARS-CoV-2 Mutants

As many previous studies have mentioned, though SARS-CoV-2 has been found to have the same cell entry mechanism as SARS-CoV-1, yet SARS-CoV-2 has a much higher transmission rate. Despite the transmission rate across SARS-like coronaviruses. Even within SARS-CoV-2 and its recently emerged variants, studies have found a higher transmission rate of the variants compared to the SARS-CoV-2 Wuhan strain. To rationale the phenomenon a genetic analysis has to be made. In addition, the emergence of multiple variants also rises concerns about vaccine neutralization activity.

Major Scientific Innovations
June 2020 – The four distinct amino acids insertion in the S1/S2 furin cleavage site compared to SARS-CoV-1 that the Whittaker has found were discovered to be essential for improving the transmission rate of SARS-CoV-2 compared to SARS-CoV-111.
August 2020 – Gave a rationale of how D614G mutant possibly causes a conformational and chemical change of the Spike protein and increases the transmission rate12.

Work Cited
  1. WHO | Pneumonia of unknown cause – China. (n.d.). WHO; World Health Organization
  2. Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., … & Zhang, L. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The lancet395(10223), 507-513.
  3. Wenjie Tan, Xiang Zhao, Xuejun Ma, Wenling Wang, Peihua Niu, Wenbo Xu, George F. Gao, Guizhen Wu. A Novel Coronavirus Genome Identified in a Cluster of Pneumonia Cases — Wuhan, China 2019−2020[J]. China CDC Weekly, 2020, 2(4): 61-62. doi: 10.46234/ccdcw2020.017
  4. Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C. L., Abiona, O., … & McLellan, J. S. (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 367(6483), 1260-1263.
  5. Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., … & Wang, X. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 581(7807), 215-220.
  6. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., … & Pöhlmann, S. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. cell, 181(2), 271-280.
  7. Daly, J. L., Simonetti, B., Klein, K., Chen, K. E., Williamson, M. K., Antón-Plágaro, C., … & Yamauchi, Y. (2020). Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science, 370(6518), 861-865.
  8. Long, Q. X., Liu, B. Z., Deng, H. J., Wu, G. C., Deng, K., Chen, Y. K., … & Huang, A. L. (2020). Antibody responses to SARS-CoV-2 in patients with COVID-19. Nature medicine, 26(6), 845-848.
  9. Conti, P., Ronconi, G., Caraffa, A. L., Gallenga, C. E., Ross, R., Frydas, I., & Kritas, S. K. (2020). Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents, 34(2), 1.
  10. Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., … & Sette, A. (2020). Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell, 181(7), 1489-1501.
  11. Jaimes, J. A., Millet, J. K., & Whittaker, G. R. (2020). Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1/S2 site. IScience, 23(6), 101212.
  12. Korber, B., Fischer, W. M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., … & Montefiori, D. C. (2020). Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell182(4), 812-827.

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