niman Posted February 28, 2020 Report Posted February 28, 2020 Pre-print on furin cleavage site in 2019-nCoV Spike gene' http://chinaxiv.org/abs/202002.00004
niman Posted February 28, 2020 Author Report Posted February 28, 2020 Download Comment Hits:45241 Downloads:12425 From: 高山 Subject: Biology >> Virology DOI：10.12074/202002.00004 Keywords: 冠状病毒; Furin蛋白酶; 切割位点; HIV; 禽流感; Cite as: chinaXiv:202002.00004 (or this versionchinaXiv:202002.00004V3) Recommended references： 李鑫,段广有,张伟,施劲松,陈嘉源,陈舜梅,高山,阮吉寿.(2020).武汉2019冠状病毒S蛋白可能存在Furin蛋白酶切位点.[ChinaXiv:202002.00004] (Click&Copy) Version History [V3] 2020-02-14 16:44:10 chinaXiv:202002.00004V3 Download [V2] 2020-02-02 18:43:17 chinaXiv:202002.00004v2(View This Version) Download [V1] 2020-01-27 22:29:24 chinaXiv:202002.00004v1(View This Version) Download
niman Posted February 28, 2020 Author Report Posted February 28, 2020 Submit Time: 2020-02-14 Author: Li Xin 1,2; Duan Guangyou 3; Zhang Wei 1; Shi Jinsong 4; Chen Jiayuan 2; Chen Shunmei 5; Gao Shan 2; Ruan Jishou 1; Institute: 1. School of Mathematical Sciences, Nankai University; 2. School of Life Sciences, Nankai University; 3. School of Life Sciences, Qilu Teachers College; 4. Eastern Hospital General Hospital; 5. Kunming Medical University Institute of Molecular Clinical Medicine;
niman Posted February 28, 2020 Author Report Posted February 28, 2020 Abstract: In December 2019, Wuhan, China reported pneumonia caused by the 2019 novel Coronavirus (2019-nCoV). Based on genomic information, our previous results showed that although 2019-nCoV and SARS coronavirus both belong to the Beta Coronavirus B subgroup (BB coronavirus), the two viruses are very different, and this result is consistent with the clinical symptoms of the two. Previous studies have also found that BB coronaviruses have a large number of variable translations, and revealed the characteristics of BB coronaviruses that mutate quickly and have high diversity at the molecular level. An important mutation in the BB coronavirus S protein was reported for the first time in this study. This mutation provided 2019-nCoV with a site for Furin protease cleavage, which is all other BB coronaviruses except mouse hepatitis coronavirus ( Including SARS and SARS-like coronavirus). This mutation has the potential to enhance the efficiency of 2019-nCoV infecting cells, which in turn makes it significantly more aggressive than SARS coronavirus. Due to this mutation, the packaging mechanism of 2019 coronavirus will also be different from most other Beta coronaviruses such as SARS, and may be the same as the packaging mechanisms of murine hepatitis coronavirus, HIV, Ebola virus and some avian influenza viruses. As an unexpected discovery, some avian influenza viruses can also obtain Furin protease cleavage sites through mutations. Subsequent research on this important mutation will lay the foundation for revealing the reasons for the strong transmission of 2019-nCoV, as well as for the development of drugs, antibodies and vaccines.
niman Posted February 28, 2020 Author Report Posted February 28, 2020 A furin cleavage site was discovered in the S protein of the Wuhan 2019 novel coronavirus Xin Li12$ , Guangyou Duan 3$ , Wei Zhang 1 , Jinsong Shi4 Jiayuan Chen 2 , Shunmei Chen 5 , Shan Gao 2*, Jishou Ruan 1* 1 School of Mathematical Sciences, Nankai University, Tianjin, Tianjin 300071, P.R.China; 2 College of Life Sciences, Nankai University, Tianjin, Tianjin 300071, P.R.China; 3 School of Life Sciences, Qilu Normal University, Jinan, Shandong 250200, P.R.China; 4 National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210016, P.R.China;
niman Posted February 28, 2020 Author Report Posted February 28, 2020 13 minutes ago, dan said: so... lab product, after all? Not at all. Strongly suspect it will be in ant eater sequence released BEFORE outbreak. Time for a dictionary check on EVOLUTION (the change in S is very small)
dabske Posted February 28, 2020 Report Posted February 28, 2020 can you please explain the meaning off Furin protease cleavage sites in plain language. Does that mean that this virus has a folow-up-scenario????
niman Posted February 28, 2020 Author Report Posted February 28, 2020 17 minutes ago, dabske said: can you please explain the meaning off Furin protease cleavage sites in plain language. Does that mean that this virus has a folow-up-scenario???? It's like the polybasic cleavage site found in high path H5 (H5N1,H5N6,H5N8 etc) or H7 (H7N9) that lets the virus get into more cell types (in this case it is cells that produce furin) and produce more damage.
dabske Posted February 28, 2020 Report Posted February 28, 2020 I'll have to check later. I'm running late for a meeting. thanks for keeping us up to date love & respect
niman Posted February 28, 2020 Author Report Posted February 28, 2020 Query 661 ECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTI 720 YP_009724390.1 661 ............................................................ 720 QHW06059.1 661 ............................................................ 720 QIA20044.1 661 ............................................................ 720 QHR84449.1 661 ............................................................ 720 QIC53204.1 661 ............................................................ 720 QHZ00379.1 661 ............................................................ 720 QHU79173.1 661 ............................................................ 720 QHR63300.2 661 ....................----.................................... 716 AVP78042.1 637 ..............H.AS----IL..TGQKA.V...........I..A..........S. 692 AVP78031.1 638 ..............H.AS----IL..TSQKA.V...........I..A..........S. 693 ATO98205.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ATO98157.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ALK02457.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ACJ60703.1 651 ..............H.AS----VL..TGQK..V...........I..A..........S. 706 AGZ48806.1 648 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 703 ATO98132.1 648 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 703 AAS00003.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ATO98218.1 648 ..............H.VSS----L..TSQK..V........DS.IV....T.......S. 703 AAP51227.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AGZ48828.1 648 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 703 AGZ48818.1 648 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 703 QDF43825.1 648 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 703 ATO98231.1 648 ..............H.VSS----L..TSQK..V........DS.IV....T.......S. 703 AAV49720.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAP13567.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACZ71976.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV49723.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAX16192.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACZ71826.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV49722.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAV98002.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAR07630.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAU04661.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAU04664.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAU04662.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ACZ72108.1 647 ..............H.VS----LL..TSQK..VV.......DS.I.....T.......S. 702 ACZ72020.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABD72985.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV97992.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 P59594.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV97995.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ABD72972.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAR23250.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV49719.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAU04649.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ACZ72254.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABD73001.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAU93319.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ACZ72195.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABF68955.1 647 ...T..........H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAR91586.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACZ71797.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAU81608.1 647 .....V........H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABD72984.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABD72970.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABD72977.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV97985.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 NP_828851.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABF68957.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAT74874.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACZ71961.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABD72969.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAP33697.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABF68956.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAU04646.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ABF68958.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV97998.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ABD72979.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV98000.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAV97984.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ACZ72093.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV97990.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AFR58672.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABF65836.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ADC35483.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAT76147.1 647 ..............H.VS----LL.NTSQK..V........DS.I.....T.......S. 702 AAV91631.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ABD72988.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV97986.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAS10463.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 AAV98001.1 647 D.............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ABD72995.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AGT21078.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABF68959.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACZ72122.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAS75868.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AEA10473.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAR07624.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACZ71991.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AFM43867.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AFR58714.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACQ82725.1 647 .....V........H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAR86775.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AEA10443.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAV97989.1 647 ..............H.VSS----L..TSQK..V........DS.I.....T.......S. 702 ACB69894.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 AAR07629.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ACB69883.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 BAE93401.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702 ABD72982.1 647 ..............H.VS----LL..TSQK..V........DS.I.....T.......S. 702
niman Posted February 28, 2020 Author Report Posted February 28, 2020 The above sequences are from the relevant region of the S protein. The first seven sequences are identical and are human nCoV sequences (at Genbank). The 8th sequence is from the closely related bat sequences which has 4 dashes signaling the absence of PRRA which creates the furin cleavage site (note that the two R's are basic amino acids). Thus,like high path H5 and H7 the coronavirus has a polybasic cleave site. This polybasic cleavage site is alsonot present in the more distantly related bat sequences.
khs Posted March 1, 2020 Report Posted March 1, 2020 On 2/28/2020 at 2:41 PM, niman said: The above sequences are from the relevant region of the S protein. The first seven sequences are identical and are human nCoV sequences (at Genbank). The 8th sequence is from the closely related bat sequences which has 4 dashes signaling the absence of PRRA which creates the furin cleavage site (note that the two R's are basic amino acids). Thus,like high path H5 and H7 the coronavirus has a polybasic cleave site. This polybasic cleavage site is alsonot present in the more distantly related bat sequences. So this could of happened via recombination with another virus that had that cleavage site?
niman Posted March 9, 2020 Author Report Posted March 9, 2020 NEWS 06 MARCH 2020 Why does the coronavirus spread so easily between people? Researchers have identified microscopic features that could make the pathogen more infectious than the SARS virus — and serve as drug targets. Smriti Mallapaty An image of the new coronavirus taken with an electron microscope.Credit: U.S. National Institutes of Health/AP/Shutterstock As the number of coronavirus infections approaches 100,000 people worldwide, researchers are racing to understand what makes it spread so easily. A handful of genetic and structural analyses have identified a key feature of the virus — a protein on its surface — that might explain why it infects human cells so readily. Other groups are investigating the doorway through which the new coronavirus enters human tissues — a receptor on cell membranes. Both the cell receptor and the virus protein offer potential targets for drugs to block the pathogen, but researchers say it is too early to be sure. “Understanding transmission of the virus is key to its containment and future prevention,” says David Veesler, a structural virologist at the University of Washington in Seattle, who posted his team’s findings about the virus protein on the biomedical preprint server bioRxiv on 20 February1. The new virus spreads much more readily than the one that caused severe acute respiratory syndrome, or SARS (also a coronavirus), and has infected more than ten times the number of people who contracted SARS. Spiky invader To infect a cell, coronaviruses use a ‘spike’ protein that binds to the cell membrane, a process that's activated by specific cell enzymes. Genomic analyses of the new coronavirus have revealed that its spike protein differs from those of close relatives, and suggest that the protein has a site on it which is activated by a host-cell enzyme called furin. This is significant because furin is found in lots of human tissues, including the lungs, liver and small intestines, which means that the virus has the potential to attack multiple organs, says Li Hua, a structural biologist at Huazhong University of Science and Technology in Wuhan, China, where the outbreak began. The finding could explain some of the symptoms observed in people with the coronavirus, such as liver failure, says Li, who co-authored a genetic analysis of the virus that was posted on the ChinaXiv preprint server on 23 February2. SARS and other coronaviruses in the same genus as the new virus don't have furin activation sites, he says. The furin activation site “sets the virus up very differently to SARS in terms of its entry into cells, and possibly affects virus stability and hence transmission”, says Gary Whittaker, a virologist at Cornell University in Ithaca, New York. His team published another structural analysis of the coronavirus’s spike protein on bioRxiv on 18 February3. Several other groups have also identified the activation site as possibly enabling the virus to spread efficiently between humans4. They note that these sites are also found in other viruses that spread easily between people, including severe strains of the influenza virus. On these viruses, the activation site is found on a protein called haemagglutinin, not on the spike protein. Urging caution But some researchers are cautious about overstating the role of the activation site in helping the coronavirus to spread more easily. “We don’t know if this is going to be a big deal or not,” says Jason McLellan, a structural biologist at the University of Texas at Austin, who co-authored another structural analysis of the coronavirus, which was published in Science on 20 February5. Other scientists are wary of comparing furin activation sites on flu viruses to those on the new coronavirus. The haemagglutinin protein on the surface of flu viruses isn’t similar or related to the spike protein in coronaviruses, says Peter White, a virologist at the University of New South Wales in Sydney, Australia. And the flu virus that caused the deadliest recorded pandemic, the 1918 Spanish flu pandemic, doesn’t even have a furin activation site, says Lijun Rong, a virologist at the University of Illinois in Chicago. Whittaker says studies in cell or animal models are needed to test the activation site’s function. “Coronaviruses are unpredictable, and good hypotheses often turn out to be wrong,” he says. His team is currently testing how removing or modifying the site affects the spike protein’s function. Drug targets Li's team are also looking at molecules that could block furin, which could be investigated as possible therapies. But their progress is slow because of the outbreak. Li lives on campus and is currently the only member able to access his team's laboratory. McLellan’s group in Texas has identified another feature that could explain why the new coronavirus infects human cells so successfully. Their experiments have shown that the spike protein binds to a receptor on human cells — known as angiotensin-converting enzyme 2 (ACE2) — at least ten times more tightly than does the spike protein in the SARS virus. Veesler’s team has also found this, which suggests that the receptor is another potential target for vaccines or therapies. For example, a drug that blocks the receptor might make it harder for coronavirus to enter cells. doi: 10.1038/d41586-020-00660-x References 1. Walls, A. C. et al. Preprint at bioRxiv https://doi.org/10.1101/2020.02.19.956581 (2020). 2. Li, H. et al. Preprint at ChinaXiv http://chinaxiv.org/abs/202002.00062 (2020). 3. Jaimes, J. A., André, N. M., Millet, J. K. & Whittaker, G. R. Preprint at bioRxiv https://doi.org/10.1101/2020.02.10.942185 (2020). 4. Coutard, B. et al. Antiviral Res. https://doi.org/10.1016/j.antiviral.2020.104742 (2020). PubMed Google Scholar 5. Wrapp, D. et al. Science https://doi.org/10.1126/science.abb2507 (2020). https://www.nature.com/articles/d41586-020-00660-x?utm_source=Nature+Briefing&utm_campaign=9dd44b4364-briefing-dy-20200309&utm_medium=email&utm_term=0_c9dfd39373-9dd44b4364-44664341
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