Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.

INTRODUCTION

The genetically diverse coronavirus (CoV) family, currently composed of four genogroups [1 (alpha), 2 (beta), 3 (gamma), and 4 (delta)], infects birds and a variety of mammals. Thus far, only CoV groups 1 and 2 are known to infect humans. Although CoV replication machinery exhibits substantial proofreading activity, replication of viral genomic RNA is inherently error-prone, driving the existence of genetically related yet diverse quasi-species (1). Most CoV strains are narrow in their host range, but zoonotic CoVs have a proclivity to jump into new host species (2). Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) are recent examples of newly emerging CoV that caused severe disease in immunologically naïve human populations. SARS-CoV emerged in Guangdong, China in 2002 and, with the aid of commercial air travel, spread rapidly throughout the globe, causing more than 8000 cases with 10% mortality (2). In 2012, it was discovered that MERS-CoV evolved to infect humans through bats by way of an intermediate camel host, causing more than 1700 cases with almost 40% mortality and, like SARS-CoV, air travel has fueled global spread to 27 countries (2). MERS-CoV is endemic in the Middle East, and serologic studies in the Kingdom of Saudi Arabia and Kenya suggest fairly frequent infections in humans (>45,000 persons) (3, 4). The SARS-CoV epidemic ended over a decade ago, but several SARS-like CoVs have been isolated from bats that efficiently use the human angiotensin-converting enzyme 2 receptor, replicate to high titer in primary human airway cells, and are resistant to existing therapeutic antibodies and vaccines (5, 6). With increasing overlap of human and wild animal ecologies, the potential for novel CoV emergence into humans is great (2). Broad-spectrum CoV therapies capable of inhibiting known human CoV would address an immediate unmet medical need and could be an invaluable treatment in the event of novel CoV emergence in the future.

Currently, there are no approved specific antiviral therapies for CoV in humans. Attempts made to treat both SARS-CoV and MERS-CoV patients with approved antivirals (that is, ribavirin and lopinavir-ritonavir) and immunomodulators (that is, corticosteroids, interferons, etc.) have not been effective in randomized controlled trials (7). Clinical development of effective CoV-specific direct-acting antivirals (DAAs) has been elusive, although there are several conserved druggable CoV enzyme targets including 3C-like protease, papain-like protease, and nonstructural protein 12 (nsp12) RNA-dependent RNA polymerase (RdRp) (7). In 2016, Warren et al. reported the in vivo antiviral efficacy of a small-molecule monophosphoramidate prodrug of an adenosine analog, GS-5734, against Ebola virus in nonhuman primates (8). Because the mechanism of action of GS-5734 for Ebola virus is the inhibition of the viral RdRp and previous work had suggested weak activity of the nucleoside component of GS-5734 against SARS-CoV (9), we sought to assess the antiviral potency and breadth of activity of GS-5734 against a diverse panel of human and zoonotic CoV.

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Science Translational Medicine  28 Jun 2017:
Vol. 9, Issue 396, eaal3653

The Dutch government on Monday said that it was "highly likely" that a person had been infected with the coronavirus by a mink, following a similar case last week.

Mink are bred for their fur at some 155 farms across the country. The authorities detected infected animals at four such locations, Agriculture Minister Carola Schouten said in a letter to parliament. At three out of four farms, a sick human was thought to be the source of the infection among the animals, while officials were still investigating the cause at the fourth one, the minister said.

The mink farms are set to close in 2023 due to a law passed before the coronavirus outbreak. Amid the latest developments, some veterinarians accused Schouten of trying to downplay the risk of the animal-to-human infection and pressured the government to clear out heavy-hit farms. However, Schouten has so far rejected the push. Addressing Dutch lawmakers on Monday, Schouten said the risk of humans getting infected outside farms was "negligible."

Dutch pets confirmed infected

Reports of humans infecting their animals, particularly cats and dogs, have appeared in various countries across the world since the beginning of the current pandemic. At least four house pets tested positive in the Netherlands last month. Minister Schouten has urged COVID-19 patients to "avoid contact with their animals."

Read more:

https://www.dw.com/en/mink-pass-coronavirus-to-humans-in-the-netherlands...

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Scientists are running a trial to see if ibuprofen can help hospital patients who are sick with coronavirus. 

The team from London's Guy's and St Thomas' hospital and Kings College believe the drug, which is an anti-inflammatory as well as a painkiller, could treat breathing difficulties.

They hope the low-cost treatment can keep patients off ventilators. 

In the trial, called Liberate, half of the patients will receive ibuprofen in addition to usual care. 

The trial will use a special formulation of ibuprofen rather than the regular tablets that people might usually buy. Some people already take this lipid capsule form of the drug for conditions like arthritis. 

Studies in animals suggest it might treat acute respiratory distress syndrome - one of the complications of severe coronavirus. 

Prof Mitul Mehta, one of the team at Kings College London, said: "We need to do a trial to show that the evidence actually matches what we expect to happen."

• Coronavirus and ibuprofen: Separating fact from fiction

Early in the pandemic there were some concerns that ibuprofen might be bad for people to take, should they have the virus with mild symptoms. 

These were heightened when France's health minister Oliver Veran said that taking non-steroidal anti-inflammatory drugs, such as ibuprofen, could aggravate the infection and advised patients to take paracetamol instead.

A review by the Commission on Human Medicines quickly concluded that, like paracetamol, it was safe to take for coronavirus symptoms. Both can bring a temperature down and help with flu-like symptoms.

For mild coronavirus symptoms, the NHS advises people try paracetamol first, as it has fewer side-effects than ibuprofen and is the safer choice for most people. You should not take ibuprofen if you have a stomach ulcer, for example.

Read more:

https://www.bbc.com/news/health-52894638

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WHO chief Tedros Adhanom Ghebreyesus said Wednesday that the trials of the anti-malarial drug for possible use against the novel coronavirus would be resumed, after they’d been paused over fears of increased death rates.

The world health body said there was no reason to modify its clinical trial of the drug, adding that experts had advised the continuation of “all arms” of the so-called Solidarity trial, including that concerning hydroxychloroquine.

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https://www.rt.com/news/490668-who-hydroxychloroquine-trials-resume-coro...

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See also:

https://thenewdaily.com.au/news/national/2020/06/04/superbugs-antibiotic-teixobactin/

On 5 June 2020, The Lancet withdrew an article it had published on May 22 [1], followed an hour later by the New England Journal of Medicine’s retraction of a similar article appeared on 1 May [2].

These two articles [3] [4] had been spotlighted by a high-profile media coverage orchestrated by the US-based Gilead Sciences laboratory. They purported to prove that certain drugs were ineffective for Covid-19, thus clearing the way for their own drugs.

Both articles were based on data collected and processed by Surgisphere, the US healthcare analytics company founded by Doctor Sapan S. Desai, who also happens to be one of the co-authors. He had already caught the public’s attention by promoting Ivermectin to inhibit Covid-19.

In a recent article, The Guardian proved that the Surgisphere data related to Australian hospitals and used in the hydroxychloroquine study was a pure fabrication. Following these revelations, the other authors of the two articles were unable to access the data collected by Surgisphere [5].

The retraction by the two scientific journals still leaves us in the dark as to what actually happened. In fact, many specialists were skeptical of these two studies at the first reading, yet deemed to be "reliable" enough to be published. It remains to be seen whether Doctor Sapan S. Desai is just a con artist who hoodwinked his colleagues, or whether the fakeries were sponsored by Gilead Science. Indeed, those studies are compatible with the interests of the laboratory; they were promoted by its press service, and were both directed by Professor Mandeep Mehra who has concealed working for Gilead Sciences.

Read more:

https://www.voltairenet.org/article210151.html

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With no vaccine or proven effective drug against the virus that causes coronavirus disease 2019 (COVID-19), scientists are racing to find clinical antiviral treatments. A promising drug target is the viral main protease Mpro, which plays a key role in viral replication and transcription. Dai et al. designed two inhibitors, 11a and 11b, based on analyzing the structure of the Mpro active site. Both strongly inhibited the activity of Mpro and showed good antiviral activity in cell culture. Compound 11a had better pharmacokinetic properties and low toxicity when tested in mice and dogs, suggesting that this compound is a promising drug candidate.

Science, this issue (Science  19 Jun 2020:

Vol. 368, Issue 6497, pp. 1331-1335) p. 1331

Abstract

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

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...

A maximum likelihood tree based on the genomic sequence showed that the virus falls within the subgenus Sarbecovirus of the genus Betacoronavirus (6). Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of coronaviruses is ~30,000 nucleotides in length with a 5′-cap structure and a 3′-poly(A) tail, and contains at least six open reading frames (ORFs) (13, 14). The first ORF (ORF 1a/b), about two-thirds of the genome length, directly translates two polyproteins, pp1a and pp1ab, so named because there is an a-1 frameshift between ORF1a and ORF1b. These polyproteins are processed by a main protease, Mpro [also known as the 3C-like protease (3CLpro)], and by one or two papain-like proteases, into 16 nonstructural proteins (NSPs). These NSPs engage in the production of subgenomic RNAs that encode four main structural proteins [envelope (E), membrane (M), spike (S), and nucleocapsid (N) proteins] and other accessory proteins (15, 16). Therefore, these proteases, especially Mpro, play a vital role in the life cycle of coronaviruses.

Mpro is a three-domain (domains I to III) cysteine protease involved in most maturation cleavage events within the precursor polyprotein (17–19). Active Mpro is a homodimer containing two protomers. The coronavirus Mpro features a noncanonical Cys-His dyad located in the cleft between domains I and II (17–19). Mpro is conserved among coronaviruses, and several common features are shared among the substrates of Mpro in different coronaviruses. The amino acids in substrates from the N terminus to the C terminus are numbered as follows: -P4-P3-P2-P1↓P1′-P2′-P3′-, with the cleavage site between P1 and P1′. In particular, a Gln is almost always required in the P1 position of the substrates. Because Mpro has no human homolog, it is an ideal antiviral target (20–22).

Design and synthesis of 11a and 11b

The active sites of Mpro are highly conserved among all coronavirus Mpros and are usually composed of four sites: S1′, S1, S2, and S4 (22). We were able to design and synthesize inhibitors targeting SARS-CoV-2 Mpro by analyzing the substrate-binding pocket of SARS-CoV Mpro (PDB ID 2H2Z) (Fig. 1). The thiol of a cysteine residue in the S1′ site anchors inhibitors by a covalent linkage that is important for the inhibitors to maintain antiviral activity. In our design of new inhibitors, an aldehyde was selected as a new warhead in P1 in order to form a covalent bond with cysteine. The reported SARS-CoV Mpro inhibitors often have an (S)-γ-lactam ring that occupies the S1 site of Mpro, and this ring was expected to be a good choice in P1 (23). Furthermore, the S2 site of coronavirus Mpro is usually large enough to accommodate the larger P2 fragment. To test the importance of different ring systems, we introduced a cyclohexyl or 3-fluorophenyl into P2, with the fluorine expected to enhance activity. An indole group was introduced into P3 to form new hydrogen bonds with S4 and improve drug-like properties.

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Australian scientists have found evidence of antibiotic-resistant bacteria in about a dozen species, including bats, penguins, sea lions and wallabies

by Graham Readfearn

For 13 years now, scientist Michelle Power has been grabbing samples of human waste and animal poop from Antarctica to Australia to try and answer a vital question.

Has the bacteria in humans that has grown resistant to antibiotics – an issue considered to be one of the world’s greatest health challenges – made its way into wildlife?

The answer, it seems, is a resounding yes.

“I don’t think there’s been an animal where we haven’t found it,” says Power, an associate professor at Macquarie University in Sydney.

The sorts of animals Power has chosen to look at most live close to humans or are urbanised – like possums – or animals that spend time with humans either in wildlife care facilities or in conservation breeding programs.

So far, Power says she has found evidence of antibiotic-resistant bacteria in about a dozen animals, including bats, penguins, sea lions and wallabies.

“You have organisms moving from us, to animals, and then potentially back to us again,” she says. “At the moment it’s hard to track what’s coming back and forth, but we know humans have driven this emergence of antibiotic-resistant bacteria.”

Power’s work on the issue started in 2007 when she looked at faeces samples of endangered brush-tailed rock wallabies being raised in captivity in New South Wales as part of conservation efforts.

About half the wallabies had antibiotic-resistant bacteria in their faeces. Those animals were released back into the wild.

In late 2009, Power fulfilled a romantic 20-year-old dream of travelling to Antarctica to do scientific research. The rather less romantic goal was to sample the human sewage from a research station there, and to “sneak up behind penguins and seals” and take their poo.

But again, her findings revealed that bacteria from humans was making its way into the Antarctic wilderness, including antibiotic-resistant bacteria.

Between 2017 and 2019, Power’s scientific colleagues together with wildlife carers have collected 448 poo samples from the little penguins of Philip Island and St Kilda, and from the penguins in zoos (one method to collect samples from wild penguins is to leave a piece of card near the entry to a nesting box because, Power says, they “like to poo out the door”).

Almost half the little penguins in captivity have antibiotic-resistant bacteria, compared with 3% of the wild population.

Power has also been part of an ongoing citizen science project encouraging others to do the faeces collecting – this time, asking for the secretions of possums.

After analysing about 1,800 samples so far, Power says the Scoop a Poop project has shown about 29% of Australia’s brush-tailed possums are carrying antibiotic-resistant bacteria.

In 2019, Power was part of a study that found antibiotic resistance in grey-headed flying foxes – a species listed as vulnerable.

In research yet to be published, Power says she has found evidence of antibiotic-resistant bacteria in wild populations of Tasmanian devils.

So how did our bacteria get into the animals?

Power says about three-quarters of the antibiotics that humans take are actually excreted, ending up in wastewater systems. Places where antibiotics are manufactured are also potential avenues for escape of antibiotics.

And then there are the times when animals are taken into care, or raised in captivity and exposed to humans, and then released into the wild.

“We are seeing a variation in the prevalence [of antibiotic-resistant bacteria] across different wildlife species but why that is the case, we are not sure,” Power says.

Read more:

https://www.theguardian.com/environment/2020/jul/19/we-cant-blame-animals-human-pathogens-are-making-their-way-into-vulnerable-wildlife

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