Coronavirus Science

[Techne]

Let's science the sht out of this year's Coronavirus . Feel free to post any interesting science about this virus.

A list of all the sequences so far:

NCBI Virus

NCBI Virus is a community portal for viral sequence data from RefSeq, GenBank and other NCBI repositories.

www.ncbi.nlm.nih.gov

Here is an annotated version.

The open reading frame 1 (ORF1) contains the sequence of a protease similar to the SARS virus.
Here is the full ORF1 sequence.

Within that sequence we have the protease of interest:
>2019-ncov_protease
QSGFRKMAFPSGKVEGCMVQVTCGTTTL
NGLWLDDVVYCPRHVICTSEDMLNPNYEDLLIRKSNHNFLVQAGNVQLRVIGHSMQNCVLKLKVDTANPK
TPKYKFVRIQPGQTFSVLACYNGSPSGVYQCAMRPNFTIKGSFLNGSCGSVGFNIDYDCVSFCYMHHMEL
PTGVHAGTDLEGNFYGPFVDRQTAQAAGTDTTITVNVLAWLYAAVINGDRWFLNRFTTTLNDFNLVAMKY
NYEPLTQDHVDILGPLSAQTGIAVLDMCASLKELLQNGMNGRTILGSALLEDEFTPFDVVRQCSGVTFQ

If you search for this sequence on any protein database you will come across a lot of solved structures of the SARS version. Comparing the sequence of the SARS version vs the Kung Flu we see the structures are quite similar.



A lot of these structures are proteins with covalently bound inhibitors. So there are already plenty of inhibitors for these types of viruses out there with the potential to be used in humans if safe. For example: http://www.rcsb.org/structure/5gwy
Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design.

First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (Mpro), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, Mpro has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 Mpro in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with Mpros from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 Mpro provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.

Sufficient clinical data for these drugs are lacking.

But currently approved anti-retrovirals can be repurposed for Coronavirus infections if needed:
Drug repurposing for new, efficient, broad spectrum antivirals.

That is exaclty what AbbVie is trying to do with their Kaletra product.

There is a possibility that vaccines previously developed against surface proteins of MERS can be useful against the Kung flu.

 

[Techne]

Interesting data:
Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event

Codon usage analyses can resolve the origin of proteins with deep ancestry with insufficient phylogenetic signal or invented de novo. The recently published bat coronavirus sequence however provides strong phylogenetic information to resolve the origin of the Spike protein as well as the rest of the genome suggesting a uniform ancestry across the genome. We have previously shown that phylogenetic discordance in deep relationships of coronaviruses is common and can be explained either by ancient recombination event or altered evolutionary rates in different lineages, or a combination of both [29]. Our study rejects the hypothesis of emergence as a result of a recent recombination event. Notably, the new coronavirus provides a new lineage for almost half of its genome, with no close genetic relationships to other viruses within the subgenus of sarbecovirus. This genomic part comprises also half of the spike region encoding a multifunctional protein responsible also for virus entry into host cells[30, 31]. The unique genetic features of 2019-nCoV and their potential association with virus characteristics and virulence in humans remain to be elucidated.

The bolded part is fueling the fires for theories thinking this may be a bioweapon. Also, ORF1-9 have close relatioships with other coronavirus proteins but ORF10 has no relationship to any coronavirus.

 

[Binary_Bark]

Full thread here:

Novel CoronaVirus (COVID-19) Updates & Discussion

SYDNEY - A man showing symptoms of a SARS-like virus after visiting China is being held in isolation at his Australian home, in the country's first suspected case of the coronavirus, public broadcaster ABC reported Tuesday. The man had recently returned from the central Chinese city of Wuhan...

mybroadband.co.za

 

[Techne]

Yeah yeah, that is for news, this thread is for the science. Some overlap of course.

 

[Techne]

Interesting figure 2 from abovementioned article:

Figure 2: Neighbor joining distance tree of the BLAST search results of the 2019-nCoV (NC_0455_Wuhan_Hu_1) sequence in the genomic region 10901-22830 of the alignment.

In the text:
A BLAST search of 2019-nCoV middle fragment revealed no considerable similarity with any of the previously characterized corona viruses (figure 2).


Also interesting is that the genomic region 10901-22830 (from figure 2) codes for:
Polymerase
Helicase
Endonuclease
Spike proteins.

The spike proteins bind to Angiotensin-converting enzyme 2 (ACE2) which allows the virus to enter human cells. The other proteins play a role in hijacking the replication machinery of the host cell to make copies of it.

 

[Prawnapple]

https://www.reddit.com/r/askscience/comments/ewwmem

Relevant Q and A

 

[Techne]

Scientists are working pretty fast to solve important structures of COVID-2019.
So far about 29 structures are available from www.rcsb.org to be used for drug design and/or drug re-assignment purposes.
Additionally, a UK group of scientists are screening and solving structures and making them available for drug design purposes.

 

[Polymathic]

Change the name of the thread to Wu-Flu to be more scientifically accurate

 

[Techne]

Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists

Scientists and senior doctors have backed claims by France’s health minister that people showing symptoms of covid-19 should use paracetamol (acetaminophen) rather than ibuprofen, a drug they said might exacerbate the condition. The minister, Oliver Veran, tweeted on Saturday 14 March that...

www.bmj.com

 

[etienne_marais]

Why Coronavirus Kills More Men Than Women

Researchers cite female immune system’s advantage, but ask if pregnancy and some men’s reluctance to see doctor are also factors

tl;dr

Sarid mentioned that differences between the male and female immune systems are also responsible for the fact that women have more autoimmune disorders than men – due to the overreaction of the immune system. Among the 10 most common autoimmune disorders, women suffer more from nine of them, sometimes much more.

Cyrille Cohen, an immunology professor at Bar-Ilan, said that among the risk factors for death from the coronavirus are high blood pressure and heart disease – which are more prevalent among men than women

That is because women’s immune systems are more active, she said. It means that the immune system that they are born with to counteract foreign intrusions is more efficient than that of men, but also that women are more prone to the system overreacting, resulting in autoimmune diseases

Another behavioral difference, she said, is seen in studies which have found that men are less likely to seek medical treatment, and that when they do, they tend to already be sicker and therefore more at risk of dying.

 

[etienne_marais]

Corona, like many other diseases, spreads in what is called geometric progression.

In mathematics, a geometric progression, also known as a geometric sequence, is a sequence of numbers where each term after the first is found by multiplying the previous one by a fixed, non-zero number called the common ratio. For example, the sequence 2, 6, 18, 54, ... is a geometric progression with common ratio 3.

The most important datum (according to Yamin, Israeli doctor) concerning a virus is the basic reproductive ratio, called R0 [pronounce R-nought] which is the average number of people a sick person will infect (more theoretical than actual).

The R0 for measles is 12 (only 5% of population can effectively be infected due to vaccinations and having had it before)
The R0 of Covid-19 is 2 but the upper limits of contamination is unknown.

According to the principle 50% of the population will be contaminated, then the R0 becomes 1 or less and can disappear and collapse at the same rate as it blew up. Immunological memory then will be the factor what happens next.

This according to bits and pieces from: https://www.haaretz.com/israel-news...s-right-about-covid-19-who-is-wrong-1.8691031 (you may want to check out the mobile version which does not require subscription).

 

[Techne]

Message from the future about Chloroquine
Antiviral Research
Volume 177, May 2020, 104762

Of chloroquine and COVID-19

Recent publications have brought attention to the possible benefit of chloroquine, a broadly used antimalarial drug, in the treatment of patients infe…

www.sciencedirect.com

 

[semaphore]

https://pubs.acs.org/doi/10.1021/acscentsci.0c00272#

 

[Techne]

https://pubs.acs.org/doi/10.1021/acscentsci.0c00272#

Nice article thanks.
Tables 3 and 4 are interesting:
Table 3. Key Protein Targets and Related Patents in the CAS Content Collection and Potential Drug Candidates in CAS REGISTRY of Chemical Substances

target​	no. of patents​	no. of potential drug candidates​
3CLpro​	49	2178
PLpro​	4	189
RdRp​	26	570
S protein​	46	333
ACE2​	5	97
AT2​	2	38

Table 4. Existing Drugs with Therapeutic Potentials for COVID-19 (Drug Repurposing)

drug candidate​	CAS RN​	target​	possible mechanism of action on COVID-19​	disease indication​
baricitinib(35)​	1187594-09-7​	JAK kinase​	a JAK inhibitor that may interfere with the inflammatory processes​	approved drug for rheumatoid arthritis​
lopinavir(19)a​	192725-17-0​	viral proteases: 3CLpro or PLpro​	protease inhibitors that may inhibit the viral proteases: 3CLpro or PLpro​	lopinavir and ritonavir are approved drug combination for HIV infection​
ritonavir(19,37)c​	155213-67-5​	​	​	​
darunavir(33)​	206361-99-1​	​	​	approved drug for HIV infection​
favipiravir (favilavir)(29,36)​	259793-96-9​	RdRp​	a purine nucleoside that acts as an alternate substrate leading to inaccurate viral RNA synthesis​	viral infections​
remdesivir(19,29,32)a​	1809249-37-3​	​	a nucleotide analogue that may block viral nucleotide synthesis to stop viral replication​	Ebola virus infection​
ribavirin(16,29−31)a​	36791-04-5​	​	​	RSV infection, hepatitis C, some viral hemorrhagic fevers​
galidesivir(34)b​	249503-25-1​	​	​	hepatitis C, Ebola virus, Marburg virus​
BCX-4430 (salt form of galidesivir)(34)b​	222631-44-9​	​	​	hepatitis C, Ebola virus, Marburg virus​
Arbidol(22,33)a​	131707-23-8​	S protein/ACE2d​	an inhibitor that may disrupt the binding of viral envelope protein to host cells and prevent viral entry to the target cell​	influenza antiviral drug​
chloroquine(29,32)​	54-05-7​	endosome/ACE2​	a drug that can elevate endosomal pH and interfere with ACE2 glycosylation​	malarial parasite infection​
nitazoxanide(29)​	55981-09-4​	N/A​	a drug that may inhibit viral protein expression​	various helminthic, protozoal, and viral infection-caused diarrhea​

a Drugs under clinical trials for treating COVID-19 (repurposing).
b Drugs under clinical trials for other virus-induced diseases.
c Ritonavir is a pharmacokinetic profile enhancer that may potentiate the effects of other protease inhibitors due to its ability to attenuate the degradation of those drugs by the liver enzyme CYP3A4 and thus is used in combination with antivirial Lopinavir.(37)
d An inhibitor of viral entry to host cells. Its direct action on S protein and ACE2 is yet to be confirmed.

 

[Techne]

Science | AAAS

www.sciencemag.org

The four promising treatments:
1) Remdesivir
2) Chloroquine and hydroxychloroquine
3) Ritonavir/lopinavir (Keletra)
4) Ritonavir/lopinavir + interferon beta

The mechanism of actions of each of these (briefly):
1) Wiki: "interferes with the action of viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production"
2) Wiki: "It increases late endosomal or lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome - release requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate."
3) Inhibits coronavirus protease, preventing maturation of viral particles.
4) Interferon beta reduces chances of a cytokine storm.

 

[Techne]

The coronavirus pandemic in five powerful charts

From papers published to carbon emissions to confirmed cases, these data reveal an unprecedented viral outbreak and its impacts around the world.

www.nature.com

 

[Techne]

Hidden coronavirus infections could be seeding new outbreaks

Scientists are rushing to estimate the proportion of people with mild or no symptoms who could be spreading the pathogen.

www.nature.com

 

[Techne]

SARS-CoV-2 Infection in Children

https://www.nejm.org/doi/full/10.1056/NEJMc2005073?query=featured_home

 

[Techne]

Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

https://www.nejm.org/doi/full/10.1056/NEJMc2004973?query=featured_home

 

[Techne]

https://www.thelancet.com/journals/lancet/article/PIIS1473-3099(20)30162-6/fulltext

• https://www.thelancet.com/journals/lancet/article/PIIS1473-3099(20)30162-6/fulltext#

Interventions to mitigate early spread of SARS-CoV-2 in Singapore: a modelling study

• Joel R Koo, BSc
• Alex R Cook, PhD
• Minah Park, PhD
• Yinxiaohe Sun, MSc
• Haoyang Sun, BSc
• Jue Tao Lim, MSc
• et al.
• Show all authors

Published:March 23, 2020DOI:https://doi.org/10.1016/S1473-3099(20)30162-6


PlumX Metrics


Summary
Background
Since the coronavirus disease 2019 outbreak began in the Chinese city of Wuhan on Dec 31, 2019, 68 imported cases and 175 locally acquired infections have been reported in Singapore. We aimed to investigate options for early intervention in Singapore should local containment (eg, preventing disease spread through contact tracing efforts) be unsuccessful.
Methods
We adapted an influenza epidemic simulation model to estimate the likelihood of human-to-human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a simulated Singaporean population. Using this model, we estimated the cumulative number of SARS-CoV-2 infections at 80 days, after detection of 100 cases of community transmission, under three infectivity scenarios (basic reproduction number [R0] of 1·5, 2·0, or 2·5) and assuming 7·5% of infections are asymptomatic. We first ran the model assuming no intervention was in place (baseline scenario), and then assessed the effect of four intervention scenarios compared with a baseline scenario on the size and progression of the outbreak for each R0 value. These scenarios included isolation measures for infected individuals and quarantining of family members (hereafter referred to as quarantine); quarantine plus school closure; quarantine plus workplace distancing; and quarantine, school closure, and workplace distancing (hereafter referred to as the combined intervention). We also did sensitivity analyses by altering the asymptomatic fraction of infections (22·7%, 30·0%, 40·0%, and 50·0%) to compare outbreak sizes under the same control measures.
Findings
For the baseline scenario, when R0 was 1·5, the median cumulative number of infections at day 80 was 279 000 (IQR 245 000–320 000), corresponding to 7·4% (IQR 6·5–8·5) of the resident population of Singapore. The median number of infections increased with higher infectivity: 727 000 cases (670 000–776 000) when R0 was 2·0, corresponding to 19·3% (17·8–20·6) of the Singaporean population, and 1 207 000 cases (1 164 000–1 249 000) when R0 was 2·5, corresponding to 32% (30·9–33·1) of the Singaporean population. Compared with the baseline scenario, the combined intervention was the most effective, reducing the estimated median number of infections by 99·3% (IQR 92·6–99·9) when R0 was 1·5, by 93·0% (81·5–99·7) when R0 was 2·0, and by 78·2% (59·0 −94·4) when R0 was 2·5. Assuming increasing asymptomatic fractions up to 50·0%, up to 277 000 infections were estimated to occur at day 80 with the combined intervention relative to 1800 for the baseline at R0 of 1·5.
Interpretation
Implementing the combined intervention of quarantining infected individuals and their family members, workplace distancing, and school closure once community transmission has been detected could substantially reduce the number of SARS-CoV-2 infections. We therefore recommend immediate deployment of this strategy if local secondary transmission is confirmed within Singapore. However, quarantine and workplace distancing should be prioritised over school closure because at this early stage, symptomatic children have higher withdrawal rates from school than do symptomatic adults from work. At higher asymptomatic proportions, intervention effectiveness might be substantially reduced requiring the need for effective case management and treatments, and preventive measures such as vaccines.