New therapy offers broad antiviral protection

Amazing stuff!

"... in the immune systems of a few dozen people scattered across the globe. ... they carried something extraordinary, an invisible shield against every virus nature could throw at them. ...

This strange biological twist first caught  ... About 15 years ago, while investigating a genetic mutation that made patients more vulnerable to bacterial infections, he stumbled upon something unexpected. The mutation caused a deficiency in a molecule called ISG15, an immune regulator. That alone was intriguing. ... the kind of inflammation these patients carried.

"The type of inflammation they had was antiviral" ..."

"For a few dozen people in the world, the downside of living with a rare immune condition comes with a surprising superpower—the ability to fight off all viruses. ..."

From the editor's summary and abstract:

"Editor’s summary

The type I interferon (IFN-I) response is a conserved cascade of signaling and gene expression that, among other functions, confers protection of cells from viral infection. After resolution of infection, the response is tamped down by regulators such as IFN-I–stimulated gene 15 (ISG15).

Cells from individuals lacking ISG15 are able to control viral infections in vitro as a consequence of maintaining a low-grade IFN-I response. Inspired by this observation, Akalu et al. identified a set of 10 ISGs that mimicked what is observed in cells from individuals lacking ISG15, with the idea that these 10 ISGs could serve as a broad-spectrum antiviral. The authors found that the 10 ISGs enabled control of multiple viral infections in vitro and lessened disease severity of SARS-CoV-2 when prophylactically administered as mRNAs to mice. Although limited delivery of the mRNAs may have restricted efficacy, as discussed by the authors, these data lay the foundation for development of a broad-spectrum antiviral prophylactic. ... 

Abstract

Type I interferons (IFN-Is) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of thousands of IFN-I–stimulated genes (ISGs), whose aggregate function results in the control of viral infections. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation.

ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, often self-resolving, mild autoinflammation. The limited breadth and low-grade persistence of ISGs expressed in ISG15 deficiency are sufficient to confer broad-spectrum antiviral resistance.

Inspired by the antiviral state of humans with ISG15 deficiency, we identified a nominal collection of 10 ISGs that recapitulated the broad antiviral potential of the IFN-I system, which typically induces the expression of thousands of ISGs. The expression of this 10-ISG collection in an IFN-I–nonresponsive cell line increased cellular resistance to Zika virus, vesicular stomatitis virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

A lipid nanoparticle–encapsulated messenger RNA (mRNA) formulation of this 10-ISG collection reduced influenza A virus plaque size in samples collected from infected mice when given prophylactically.

Moreover, when used collectively and delivered prophylactically, the 10-ISG collection was able to protect hamsters against a lethal SARS-CoV-2 challenge, in contrast with the lack of efficacy when mRNAs were delivered individually. These findings suggest that these 10 ISGs have potential as a broad-spectrum antiviral prophylactic."

New therapy offers broad antiviral protection

One Universal Antiviral to Rule Them All? (original news release) "Taking inspiration from a rare mutation that makes people impervious to viral diseases, a Columbia researcher is developing a therapy that could bestow this superpower on the rest of us"

An mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo (no public access)

Broad-spectrum RNA antiviral inspired by ISG15-/- deficiency (preprint, open access)

Fig 1 ISG15 deficiency inspires the identification of a nominal collection of 10 ISGs with broad-spectrum antiviral potential.

Scientists discover compounds that help cells fight a wide range of viruses

Amazing stuff! The systematic discovery of antivirals makes further progress.

"Researchers ... have identified compounds that can fight off viral infection by activating a defense pathway inside host cells. These compounds, they believe, could be used as antiviral drugs that work against not just one but any kind of virus.

The researchers identified these compounds, which activate a host cell defense system known as the integrated stress response pathway, in a screen of nearly 400,000 molecules. In tests in human cells, the researchers showed that the compounds help cells fend off infection from RSV, herpes virus, and Zika virus. They also proved effective in combating herpes infection in a mouse model. ...

By measuring the cells’ survival rates, the researchers could determine which compounds boosted activation of the pathway and amplified the cells’ ability to shut down viral reproduction. This screen yielded about 3,500 compounds with potential antiviral activity, which were evaluated further. ..."

From the highlights and abstract:

"Highlights

• An optogenetics platform specifically induces the integrated stress response

• This platform enables a high-throughput screen of 370,830 compounds

• Identified compounds selectively eliminate ISR-high cells across diverse stressors

• These compounds demonstrate broad-spectrum antiviral activity in vitro and in mice

Summary

The integrated stress response (ISR) is a conserved stress response that maintains homeostasis in eukaryotic cells.

Modulating the ISR holds therapeutic potential for diseases including viral infection, cancer, and neurodegeneration, but few known compounds can do so without toxicity.

Here, we present an optogenetic platform for the discovery of compounds that selectively modulate the ISR. Optogenetic clustering of PKR induces ISR-mediated cell death, enabling the high-throughput screening of 370,830 compounds.

We identify compounds that potentiate cell death without cytotoxicity across diverse cell types and stressors. Mechanistic studies reveal that these compounds upregulate activating transcription factor 4 (ATF4), sensitizing cells to stress and apoptosis, and identify GCN2 as a molecular target.

Additionally, these compounds exhibit antiviral activity, and one compound reduced viral titers in a mouse model of herpesvirus infection. Structure-activity and toxicology studies highlight opportunities to optimize therapeutic efficacy. This work demonstrates an optogenetic approach to drug discovery and introduces ISR potentiators with therapeutic potential."

Scientists discover compounds that help cells fight a wide range of viruses | MIT News | Massachusetts Institute of Technology "The molecules trigger a built-in cellular stress response and show promise as broad-spectrum antivirals against Zika, herpes, RSV, and more."

Optogenetics-enabled discovery of integrated stress response modulators (no public access)

Link to PDF

Graphical abstract

A newly characterized anti-viral defense system in bacteria

Amazing stuff! Apparently a suicidal, late stage, last resort defense system.

"... Phages and bacteria are engaged in a constant battle, the virus attempting to circumvent the bacteria’s defenses, and the bacteria racing to find new ways to protect itself. ...

has characterized an anti-phage defense system in bacteria, CmdTAC. CmdTAC prevents viral infection by altering the single-stranded genetic code used to produce proteins, messenger RNA.

This defense system detects phage infection at a stage when the viral phage has already commandeered the host’s machinery for its own purposes. In the face of annihilation, the ill-fated bacterium activates a defense system that will halt translation, preventing the creation of new proteins and aborting the infection — but dooming itself in the process. ...

CmdTAC is a subset of a widespread anti-phage defense mechanism called a toxin-antitoxin system. A TA system is just that: a toxin capable of killing or altering the cell’s processes rendered inert by an associated antitoxin. ...

CmdTAC is a TA system with an additional element, and the three components generally exist in a stable complex: the toxic CmdT, the antitoxin CmdA, and an additional component called a chaperone, CmdC.

If the phage’s protective capsid protein is present, CmdC disassociates from CmdT and CmdA and interacts with the phage capsid protein instead. In the model outlined in the paper, the chaperone CmdC is, therefore, the sensor of the system, responsible for recognizing when an infection is occurring.  ...

The uncoupling of CmdC exposes the neutralizing antitoxin CmdA to be degraded, which releases the toxin CmdT to do its lethal work.  ..."

From the abstract:

"Host–pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacterial defence against bacteriophages. Here we characterize the widely distributed anti-phage defence system CmdTAC, which provides robust defence against infection by the T-even family of phages. Our results support a model in which CmdC detects infection by sensing viral capsid proteins, ultimately leading to the activation of a toxic ADP-ribosyltransferase effector protein, CmdT. We show that newly synthesized capsid protein triggers dissociation of the chaperone CmdC from the CmdTAC complex, leading to destabilization and degradation of the antitoxin CmdA, with consequent liberation of the CmdT ADP-ribosyltransferase. Notably, CmdT does not target a protein, DNA or structured RNA, the known targets of other ADP-ribosyltransferases. Instead, CmdT modifies the N6 position of adenine in GA dinucleotides within single-stranded RNAs, leading to arrest of mRNA translation and inhibition of viral replication. Our work reveals a novel mechanism of anti-viral defence and a previously unknown but broadly distributed class of ADP-ribosyltransferases that target mRNA."

Killing the messenger | MIT News | Massachusetts Institute of Technology "A newly characterized anti-viral defense system in bacteria aborts infection through a novel mechanism by chemically altering mRNA."

Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation (open access)

A proposed model for CmdTAC contains three elements: the toxic CmdT (red), the antitoxin CmdA (blue), and a chaperone, CmdC (green). During infection, CmdC uncouples from CmdT and CmdA, exposing the neutralizing antitoxin CmdA to be degraded, which releases the toxin CmdT to do its lethal work.

Fig. 5: Model for anti-phage defence by the CmdTAC system.

What Enables Herpes Simplex Virus To Become Impervious to Drugs?

Good news! Just look at the beautiful 3D virus representation at the bottom.

"At a glance:

• New research explains how herpes simplex virus can develop resistance to antiviral medicines.
• Study shows that movements in specific parts of a protein that enable viral replication can alter susceptibility to drugs.
• The findings answer long-standing questions about viral drug resistance and can inform new approaches to designing more effective therapies.

...

Using a sophisticated imaging technique called cryogenic electron microscopy (cryo-EM), the researchers found that how parts of a protein responsible for viral replication move into different positions can alter the virus’s susceptibility to medicines. ...

Instead, the investigators discovered that protein mutations linked to drug resistance often arise far from the drug’s target location. These mutations involve alterations that change the movements of a viral protein, or enzyme, that allows the virus to replicate itself. This raises the possibility that using drugs to block or freeze the conformational changes of these viral proteins could be a successful strategy for overcoming drug resistance. ...

Conformational dynamics — the ability of different parts of a protein to move — allow them to efficiently administer many essential functions with a limited number of ingredients. A better understanding of polymerase conformational dynamics is the missing link between structures and functions, including whether a protein responds to a drug and whether it could become resistant to it down the road. ...

First, using cryo-EM, they conducted structural analysis to get high-resolution visualizations of the atomic structures of HSV polymerase in multiple conformations, as well as when bound to the antiviral drugs acyclovir and foscarnet. The drug-bound structures revealed how the two drugs selectively bind polymerases that more readily adopt one conformation versus another. One of the drugs, foscarnet, works by trapping the fingers of the DNA polymerase so that they are stuck in a so-called closed configuration.

Further, structural analysis paired with computational simulations suggested that several mutations that are distant from the sites of drug binding confer antiviral resistance by altering the position of the polymerase fingers responsible for closing onto the drug to halt DNA replication.

The finding was an unexpected twist. Up until now, scientists have believed that polymerases closed partially only when they attached to DNA and closed fully only when they added a DNA building block, a deoxynucleotide. It turns out, however, that HSV polymerase can fully close just by being near DNA. This makes it easier for acyclovir and foscarnet to latch on and stop the polymerase from working, thus halting viral replication. ..."

From the highlights and abstract:

"Highlights

• Cryo-EM structures reveal how HSV polymerase interacts with DNA and antivirals

• Polymerase is in multiple conformations when not bound to nucleotide or antiviral

• Antiviral resistance mutations alter polymerase conformational dynamics

Summary

DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. We determined cryoelectron microscopy (cryo-EM) structures of DNA-bound herpes simplex virus polymerase holoenzyme in multiple conformations and interacting with antivirals in clinical use. These structures reveal how the catalytic subunit Pol and the processivity factor UL42 bind DNA to promote processive DNA synthesis. Unexpectedly, in the absence of an incoming nucleotide, we observed Pol in multiple conformations with the closed state sampled by the fingers domain. Drug-bound structures reveal how antivirals may selectively bind enzymes that more readily adopt the closed conformation. Molecular dynamics simulations and the cryo-EM structure of a drug-resistant mutant indicate that some resistance mutations modulate conformational dynamics rather than directly impacting drug binding, thus clarifying mechanisms that drive drug selectivity."

What Enables Herpes Simplex Virus To Become Impervious to Drugs? | Harvard Medical School "Findings about how cold sore virus evades treatment offer broader clues on drug resistance"

Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance (open access)

Graphical abstract

A 3D representation of a herpes simplex virus enzyme involved in viral replication.

Bacteria use an unusual new molecular mechanism to fight viruses

Amazing stuff!

"Viruses plague bacteria as well as people, and some bacteria deploy ... molecular mechanism to defend themselves, two studies published in Science this month reveal. The bacteria conjure up an entirely new gene that isn’t normally in their repertoire. This gene, dubbed neo by both groups that unearthed it, then spawns a protein that stymies the viral invaders. ...

To assemble their new gene, the studies show, the bacteria exploit enzymes called reverse transcriptases, which invert a key cellular mechanism. Cells usually start with information encoded in a gene’s DNA to make RNA molecules, such as the messenger RNAs (mRNAs) that carry the instructions for synthesizing a protein. But reverse transcriptases can flip the process around and produce DNA versions of RNA molecules. Discovered in tumor-causing viruses, the enzymes also allow HIV to commandeer human cells. However, many bacteria also make reverse transcriptases, and the new work reveals how at least one kind of bacterium uses them to turn the tables on the viruses known as phages. ..."

"In a genetic sleight of hand used to ward off invading viruses, certain bacteria can assemble a gene to make an antiviral protein, two groups publishing in Science this month have shown. The unprecedented defensive maneuver ... The findings offer the latest challenge to the misperception that genetic information flows only one way—from DNA to RNA to proteins—and raise the possibility that similar cryptic genes lurk in other organisms, even humans. ..."

From the abstract:

"Reverse transcription has frequently been co-opted for cellular functions and in prokaryotes is associated with protection against viral infection, but the underlying mechanisms of defense are generally unknown. Here, we show that in the DRT2 defense system the reverse transcriptase binds a neighboring pseudoknotted noncoding RNA. Upon bacteriophage infection, a template region of this RNA is reverse transcribed into an array of tandem repeats that reconstitute a promoter and open reading frame, allowing expression of a toxic repetitive protein and an abortive infection response. Biochemical reconstitution of this activity and cryogenic electron microscopy provide a molecular basis for repeat synthesis. Gene synthesis from a noncoding RNA is a new mode of genetic regulation in prokaryotes."

ScienceAdvisor

Bacteria use ‘crazy molecular mechanism’ to fight viruses "Made-to-order gene could be so toxic that cells only assemble it in emergencies"

Phage-triggered reverse transcription assembles a toxic repetitive gene from a noncoding RNA (no public access)

Some bacteria (orange ball) defend themselves against phages, by assembling a gene not in their normal genome

Beyond aspirin: Willow bark also found to be a broad-spectrum antiviral

Amazing stuff! The article below dates back to November 2023.

"Now, a Finnish study led by researchers ... has found that willow bark extract might also be an effective, broad-spectrum antiviral agent. ...

In a previous study, the researchers had tested willow bark (Salix) extract on non-enteroviruses, a group of RNA viruses such as those that cause polio and hepatitis A, and found it to be very effective and non-toxic.  ...

The researchers then tested it on cell samples with two strains of enteroviruses, Coxsackievirus A (CVA) and B (CVB), and two coronaviruses, a seasonal coronavirus and SARS-CoV-2, which causes COVID-19. ...
The researchers found that the Salix extract exhibited different mechanisms of action on different virus types. Enteroviruses couldn’t enter cells after they’d been treated with the extract; in the SARS-CoV-2 samples, the virus could enter the treated cells, but it couldn’t reproduce once inside. ...

When the researchers experimented with the timing of adding the extract, they found that it appeared to act on the virus’ surface rather than at a particular stage of its replication cycle. ...

As yet, the researchers have been unable to ascertain which compounds in the extract produce the antiviral effect, so further research will be needed. ..."

From the abstract:

"Introduction: Recurring viral outbreaks have a significant negative impact on society. This creates a need to develop novel strategies to complement the existing antiviral approaches. There is a need for safe and sustainable antiviral solutions derived from nature.

Objective: This study aimed to investigate the antiviral potential of willow (Salix spp.) bark hot water extracts against coronaviruses and enteroviruses. Willow bark has long been recognized for its medicinal properties and has been used in traditional medicines. However, its potential as a broad-spectrum antiviral agent remains relatively unexplored.

Methods: Cytopathic effect inhibition assay and virucidal and qPCR-based assays were used to evaluate the antiviral potential of the bark extracts. The mechanism of action was investigated using time-of-addition assay, confocal microscopy, TEM, thermal, and binding assays. Extracts were fractionated and screened for their chemical composition using high-resolution LC-MS.

Results: The native Salix samples demonstrated their excellent antiviral potential against the non-enveloped enteroviruses even at room temperature and after 45 s. They were equally effective against the seasonal and pandemic coronaviruses. Confocal microscopy verified the loss of infection capacity by negligible staining of the newly synthesized capsid or spike proteins. Time-of-addition studies demonstrated that Salix bark extract had a direct effect on the virus particles but not through cellular targets. Negative stain TEM and thermal assay showed that antiviral action on enteroviruses was based on the added stability of the virions. In contrast, Salix bark extract caused visible changes in the coronavirus structure, which was demonstrated by the negative stain TEM. However, the binding to the cells was not affected, as verified by the qPCR study. Furthermore, coronavirus accumulated in the cellular endosomes and did not proceed after this stage, based on the confocal studies. None of the tested commercial reference samples, such as salicin, salicylic acid, picein, and triandrin, had any antiviral activity. Fractionation of the extract and subsequent MS analysis revealed that most of the separated fractions were very effective against enteroviruses and contained several different chemical groups such as hydroxycinnamic acid derivatives, flavonoids, and procyanidins.

Conclusion: Salix spp. bark extracts contain several virucidal agents that are likely to act synergistically and directly on the viruses."

Beyond aspirin: Willow bark also found to be a broad-spectrum antiviral (published 11/9/2023)

Willow (Salix spp.) bark hot water extracts inhibit both enveloped and non-enveloped viruses: study on its anti-coronavirus and anti-enterovirus activities (open access, published 11/8/2023)

Origami DNA Traps Could Keep Large Viruses like SARS-CoV-2 or influenza From Infecting Cells

This seems to be a promising new approach of viral entrapment! Put a shell/envelop/casing/cage around the virus!

"... A study published today (January 18) in Cell Reports Physical Science details how researchers used DNA origami to engineer strands of genetic material into Lego-like structures that form a cage around large pathogens. While the study only looked at how effectively the structures bound to viruses in vitro, the traps could one day help clear viruses from the body. ...
Using DNA origami, the team designed 2D triangle-shaped building blocks that snap together, edge to edge, like puzzle pieces. Then, using cryo-electron microscopy (cryoEM), the researchers confirmed that the triangles assembled themselves into cone-shaped, multisided shells. The team then coated the inside of each shell with virus-binding substances such as antibodies. These shells can sandwich themselves together around viruses, encasing a viral particle more than 100 nm in diameter, which could, in theory, cordon the virus off from a potential host cell and prevent infection, though the team didn’t test for clinical outcomes. Importantly, the shells could also be coated with other virus-binding substances. In this case, the researchers used heparan sulfate, a substance that sticks to many viral protein coats. ...
One hurdle in the assembly process was the finding that the shells, assembled in solutions with high salinity, fell apart under physiological conditions, especially when exposed to low salinity. So, to stabilize the assembled cones further, the researchers used UV light to strengthen the bonds between the building blocks, which prevented the shells from degrading at the relatively low salt concentrations found in the body. They also covered the assembled structures with an oligosine polymer-based coating, preventing them from being degraded by nucleases. On the whole, the process was faster and more efficient than existing DNA origami-based virus-capture techniques, which use multiple types of building blocks ..."

From the abstract:

"Virus-enveloping macromolecular shells or tilings can prevent viruses from entering cells. Here, we describe the design and assembly of a cone-shaped DNA origami higher-order assembly that can engulf and tile the surface of pleomorphic virus samples larger than 100 nm. We determine the structures of subunits and of complete cone assemblies using cryoelectron microscopy (cryo-EM) and establish stabilization treatments to enable usage in in vivo conditions. We use the cones exemplarily to engulf influenza A virus particles and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), chikungunya, and Zika virus-like particles. Depending on the relative dimensions of cone to virus particles, multiple virus particles may be trapped per single cone, and multiple cones can also tile and adapt to the surface of aspherical virus particles. The cone assemblies form with high yields, require little purification, and are amenable for mass production, which is a key requirement for future real-world uses including as a potential antiviral agent."

“Origami” DNA Traps Could Keep Large Viruses From Infecting Cells | The Scientist Magazine® By engineering structures out of DNA, scientists could potentially prevent larger viruses, like coronaviruses and influenza viruses, from interacting with cells.

DNA origami traps for large viruses (open access)

Graphical abstract

Scientists discover new antiviral defense system in bacteria

Good news! Amazing stuff!

"Bacteria use a variety of defense strategies to fight off viral infection, and some of these systems have led to groundbreaking technologies, such as CRISPR-based gene-editing. Scientists predict there are many more antiviral weapons yet to be found in the microbial world. ...
They found that certain proteins in bacteria and archaea (together known as prokaryotes) detect viruses in surprisingly direct ways, recognizing key parts of the viruses and causing the single-celled organisms to commit suicide to quell the infection within a microbial community. The study is the first time this mechanism has been seen in prokaryotes and shows that organisms across all three domains of life — bacteria, archaea, and eukaryotes (which includes plants and animals) — use pattern recognition of conserved viral proteins to defend against pathogens. ...

Two viral proteins elicited an immune response: the portal, a part of the virus’s capsid shell, which contains viral DNA; and the terminase, the molecular motor that helps assemble the virus by pushing the viral DNA into the capsid. Each of these viral proteins activated a different STAND ATPase to protect the cell.

The finding was striking and unprecedented. Most known bacterial defense systems work by sensing viral DNA or RNA, or cellular stress due to the infection. These bacterial proteins were instead directly sensing key parts of the virus. ..."

"The innate immune systems of animals, plants, and fungi universally use nucleotide binding oligomerization domain–like receptors (NLRs) of the STAND superfamily to detect molecular patterns common to pathogens. Gao et al. show that NLR-based immune pattern recognition is also prevalent in bacteria and archaea, something that was not known before. In particular, the authors characterized four families of NLR-like genes, finding that they are specific sensors for two highly conserved bacteriophage proteins. Upon binding to the target, these NLRs activate diverse effector domains, including nucleases, to prevent phage propagation. These findings demonstrate that pattern recognition of pathogen-specific proteins is a common mechanism of immunity across all domains of life."

From the abstract:

"INTRODUCTION

Many organisms have evolved specialized immune pattern-recognition receptors, including nucleotide-binding oligomerization domain-like receptors (NLRs) of the STAND superfamily that are ubiquitous in plants, animals, and fungi. NLRs oligomerize upon recognition of pathogen-associated molecular patterns, leading to the activation of an effector domain that mediates an inflammatory or cell death response. Although the roles of NLRs in eukaryotic immunity are well established, it is unknown whether prokaryotes use similar defense mechanisms.

RATIONALE

We previously identified a set of bacterial and archaeal STAND nucleoside triphosphatases (NTPases), dubbed Avs (antiviral STAND), that protect bacteria from tailed phages through an unknown mechanism. Like eukaryotic NLRs, Avs proteins have a characteristic tripartite domain architecture consisting of a central NTPase, an extended C-terminal sensor, and an N-terminal effector. Here, we investigate the defense mechanism of these Avs proteins.

RESULTS

Using genetic screens in Escherichia coli, we characterized four Avs families (Avs1 to Avs4) and found that they detect hallmark viral proteins that are expressed during infection. In particular, Avs1 to Avs3 recognize the large terminase subunit, and Avs4 recognizes the portal. These two proteins together make up the conserved DNA packaging machinery of tailed phages. Coexpression of an Avs protein with its cognate target in E. coli resulted in cell death.

We assessed the specificity of Avs target recognition with a panel of terminases and portals from 24 tailed phages, spanning nine major families. Notably, a single Avs protein was capable of recognizing a large variety of targets (terminase or portal), with less than 5% sequence identity in some cases.

We next reconstituted Avs activity in vitro, focusing on representatives from Salmonella enterica (SeAvs3) and E. coli (EcAvs4), both of which contain N-terminal PD-DExK nuclease effectors. In the presence of their cognate target, SeAvs3 and EcAvs4 mediated degradation of double-stranded DNA. Nuclease activity required the presence of Mg2+ and adenosine triphosphate (ATP); however, the hydrolysis of ATP was not strictly required. Single-stranded DNA and RNA substrates were not cleaved.

We determined the cryo–electron microscopy structures of the SeAvs3-terminase and EcAvs4-portal complexes, revealing that both form tetramers in which the C-terminal sensor domain of each Avs subunit binds to a single target protein. Binding is mediated by shape complementarity across an extended interface, consistent with fold recognition. Additionally, SeAvs3 directly recognizes terminase active-site residues and its ATP ligand. Tetramerization of both SeAvs3 and EcAvs4 is mediated by their STAND ATPase domains and allows the N-terminal nucleases to adopt active dimeric configurations.

Bioinformatic analysis of Avs proteins across prokaryotic lineages revealed at least 18 distinct types of N-terminal effectors that are modularly swapped between Avs homologs, as well as widespread distribution of avs genes across phyla with extensive horizontal gene transfer. Finally, we also discovered phage-encoded Avs inhibitors, highlighting an extensive arms race between prokaryotes and viruses.

CONCLUSION

NLR-like defense proteins in bacteria and archaea recognize the conserved folds of hallmark viral proteins and assemble into tetramers that activate diverse N-terminal effectors. The mechanism of these proteins highlights the similarity between the defense strategies of prokaryotes and eukaryotes and extends the paradigm of pattern recognition of pathogen-specific proteins across all three domains of life."

MIT scientists discover new antiviral defense system in bacteria | MIT News | Massachusetts Institute of Technology

Prokaryotic innate immunity through pattern recognition of conserved viral proteins (no public access)

COVID antiviral pills: what scientists still want to know

If these new medications have to be given early at the onset of the infection this defeats the purpose to some extent! Since 60-95% of infected experience no or only mild symptoms it would not make much sense to provide them with those new, possibly expensive medications.

Some more fine tuning and more innovative medications are needed, but SARS-CoV-2/Covid-19 is essentially under control given the available vaccines and medications. Let's finally and fast return to normal life before the pandemic!

"... Because antiviral drugs often need to be given early in the course of an infection for them to work effectively, Mellors will also be looking for more detail about when the drugs were given in the trials, and at how those timings correlated with efficacy. That information will provide a sense of when the window of opportunity for treatment closes. ...
Researchers are also keen for any clue — including from further clinical trials — as to whether the drugs affect transmission of the coronavirus, or prevent illness in people who have been exposed to it. ...

Molnupiravir acts by introducing mutations into the viral genome during viral replication. A metabolite of the drug is picked up by a viral enzyme called RNA-dependent RNA polymerase and incorporated into the viral genome, eventually causing so many errors that the virus can no longer survive.

Human cells have a DNA, rather than an RNA, genome, but some laboratory experiments have suggested that molnupiravir could cause mutations in human DNA as well.

A full course of treatment with molnupiravir is only five days long. ...
Paxlovid acts by inhibiting an enzyme that’s needed to process some viral proteins into their final, functional form. But the drug is a combination of an antiviral and another drug, called ritonavir, which helps to prevent enzymes in the liver from breaking down the antiviral before it has a chance to disable the coronavirus. Ritonavir, a component of some HIV treatment cocktails, can affect how some other medications are metabolized by the body. A wide range of drugs should not be given with it, including some that are commonly used to treat heart conditions, suppress the immune system and reduce pain. ...
The targets of molnupiravir and Paxlovid are different, but researchers will still need to show that the drugs work against variants ..."

COVID antiviral pills: what scientists still want to know

The FDA Blocks a Promising COVID-19 Treatment

For two years, the citizens of Western democracies have been subjected to massive government failure to deal with the pandemic! More about this e.g. here. One of the few exceptions: President Trump's rush to develop a new vaccine and to approve it in record time!

The article below is not specifically about the FDA's latest blunder, but about a historic review of such blunders.

"Last week, the United Kingdom approved a new antiviral pill (molnupiravir). Studies show the drug reduces the risk of hospitalization and death among high‐​risk COVID patients by half. U.S. taxpayers funded molnupiravir’s development. Yet the U.S. Food and Drug Administration isn’t even meeting to consider approval until Nov. 30.

Molnupiravir is the latest example of the FDA denying patients their most important health care right — the right to make their own health decisions — by prohibiting them from getting drugs that have received approval in other advanced countries. ...
In the 1980s, an HIV-AIDS diagnosis was a death sentence. Patients were dying by the tens of thousands. Yet the FDA infamously denied AIDS patients access to treatments that were available in China, Israel, Japan, Mexico and Sweden. ..."

Again and Again, the FDA Fails American Patients | Cato Institute Molnupiravir is saving lives in the United Kingdom; the FDA is blocking it here.

More COVID antiviral drugs are coming

Never before in human history was a new, highly infectious virus defeated so fast! Remember e.g. HIV/AIDS, it took 1-2 decades!

It is long overdue to return to normal life before the pandemic since the beginning or latest March of this year! There is simply no justification anymore for the continuation of draconian measures taken by paternalistic governments unless the true aim is to fight so called climate change, the greatest demagoguery of our time! But this is another subject well covered here (see labels Global Warming hoax and Climate Change religion)

"... On 4 November, the United Kingdom became the first country to approve molnupiravir, which was developed by Merck ... Ridgeback Biotherapeutics ... The approval came just over a month after the companies announced that the antiviral drug, which will be branded Lagevrio, halved the risk of hospitalization in people with mild or moderate forms of COVID-19. A day after the UK approval, Pfizer, based in New York City, announced that its antiviral drug Paxlovid cut hospitalizations by 89%. ..."

COVID antiviral pills: what scientists still want to know Drugs such as molnupiravir and Paxlovid could change the course of the pandemic if clinical trial results hold up in the real world.

Forscher entdecken Wirkstoffe gegen Corona-Proteasen

Good news! 

"Forscher der Universitäten in Gießen, Mainz und Würzburg haben Hemmstoffe entdeckt, die als Grundlage für neue Medikamente gegen Covid-19 dienen könnten. Die Substanzen greifen Enzyme an, die das Virus für seine Vermehrung benötigt, wie die Universität Mainz mitteilt. ...
Die Wissenschaftler überprüften 40 bis 45 Substanzen daraufhin, ob sie die Proteasen lahmlegen und die Vermehrung der Viren stoppen können. Es konnten mehrere sogenannte nichtpeptidische Moleküle identifiziert werden, mit denen sich beides erreichen lässt. ..."

"... The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PLpro are valuable starting points for the development of new pan‐coronaviral inhibitors. ..."

Forscher entdecken Wirkstoffe gegen Corona-Proteasen Um die Corona-Pandemie zu bekämpfen, werden nicht nur Impfstoffe, sondern auch Medikamente gebraucht. Wissenschaftler von drei deutschen Unis haben mehrere Wirkstoff-Kandidaten gefunden.

Hier ist der Link zu dem bezüglichen Wissenschaftsartikel:

Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2