Scientists at Trinity College Dublin have discovered a new process in the immune system that leads to the production of an important family of anti-viral proteins called interferons. They hope the discovery will now lead to new, effective therapies for people with some autoimmune and infectious diseases.
Reporting in Nature Metabolism, Luke O’Neill, Professor of Biochemistry in the School of Biochemistry and Immunology at Trinity, and his team have found that a natural metabolite called Itaconate can stimulate immune cells to make interferons by blocking an enzyme called SDH.
Co-lead author, Shane O’Carroll, from Trinity’s School of Biochemistry and Immunology, said: “We have linked the enzyme SDH to the production of interferons in an immune cell type called the macrophage. We hope our work will help the effort to develop better strategies to fight viruses because interferons are major players in how our innate immune system eliminates viruses – including COVID-19.”
Co-lead author, Christian Peace, from Trinity’s School of Biochemistry and Immunology, added: “Itaconate is a fascinating molecule made by macrophages during infections. It’s already known to suppress damaging inflammation but now we have found how it promotes anti-viral interferons.”
Working with drug companies Eli Lilly and Sitryx Ltd, the next step is to test new therapies based on Itaconate in various diseases, with some autoimmune diseases and some infectious diseases on the likely list. And the work potentially extends to other disease contexts in which SDH is inhibited, such as cancer, and could reveal a new therapeutic target for SDH-deficient tumours.
Prof O’Neill said: “With Itaconate you get two for the price of one – not only can it block harmful inflammation, but it can also help fight infections. We have discovered important mechanisms for both and the hope now is that patients will benefit from new therapies that exploit Itaconate and its impacts.”
Clinical trials in patients are set to start next year.
Thinking about getting a new desk for your practice? That might be a good idea. Viruses, including SARS-CoV-2, can get passed from person to person via contaminated surfaces. But can some surfaces reduce the risk of this type of transmission without the help of household disinfectants? As reported in ACS Applied Materials & Interfaces, wood has natural antiviral properties that can reduce the time viruses persist on its surface – and some species of wood are more effective than others at reducing infectivity.
Enveloped viruses, like the coronavirus, can live up to five days on surfaces; nonenveloped viruses, including enteroviruses linked to the common cold, can live for weeks, in some cases even if the surfaces are disinfected. Previous studies have shown that wood has antibacterial and antifungal properties, making it an ideal material for cutting boards. But wood’s ability to inactivate viruses has yet to be explored, which is what Varpu Marjomäki and colleagues set out to study.
The researchers looked at how long enveloped and nonenveloped viruses remained infectious on the surface of six types of wood: Scots pine, silver birch, gray alder, eucalyptus, pedunculate oak and Norway spruce. To determine viral activity, they flushed a wood sample’s surface with a liquid solution at different time points and then placed that solution in a petri dish that contained cultured cells. After incubating the cells with the solution, they measured the number (if any) infected with the virus.
Results from their demonstrations with an enveloped coronavirus showed that pine, spruce, birch and alder need one hour to completely reduce the virus’ ability to infect cells, with eucalyptus and oak needing two hours. Pine had the fastest onset of antiviral activity, beginning after five minutes. Spruce came in second, showing a sharp drop in infectivity after 10 minutes.
For a nonenveloped enterovirus, the researchers found that incubation on oak and spruce surfaces resulted in a loss of infectivity within about an hour, with oak having an onset time of 7.5 minutes and spruce after 60 minutes. Pine, birch and eucalyptus reduced the virus’ infectivity after four hours, and alder showed no antiviral effect.
Based on their study data, the researchers concluded that the chemical composition of a wood’s surface is primarily responsible for its antiviral functionality. While determining the exact chemical mechanisms responsible for viral inactivation will require further study, they say these findings point to wood as a promising potential candidate for sustainable, natural antiviral materials.
Colourised scanning electron micrograph of HIV (yellow) infecting a human T9 cell (blue). Credit: NIH
Australian researchers have discovered a previously unknown rogue immune cell that can cause poor antibody responses in chronic viral infections. The finding, published in the journal, Immunity, may lead to earlier intervention and possibly prevention of some types of viral infections such as HIV or hepatitis.
One of the remaining mysteries of the human immune system is why ‘memory’ B cells often only have a weak capacity to protect us from persistent infections.
In an answer to this, researchers from the Monash University Biomedicine Discovery Institute have now discovered that chronic viral infection induces a previously unknown immune B memory cell that does not produce high levels of antibodies.
Importantly the research team, led by Professor Kim Good-Jacobson and Dr Lucy Cooper, also determined the most effective time during the immune response for therapeutics such as anti-viral and anti-cancer drugs to better boost immune memory cell development.
“What we discovered was a previously unknown cell that is produced by chronic viral infection. We also determined that early intervention with therapeutics was the most effective to stop this type of memory cell being formed, whereas late intervention could not,” Professor Good-Jacobson said.
According to Dr Cooper, chronic viral infections have been known to alter our ability to form effective long-term protective antibody responses, but how that happens is unknown.
“In the future, this research may result in new therapeutic targets, with the aim to reduce the devastating effect of chronic infectious diseases on global health, specifically those that are not currently preventable by vaccines,” she said.
“Revealing this new immune memory cell type, and what genes it expresses, allows us to determine how we can target it therapeutically and whether that will lead to better antibody responses.”
The research team are also looking to see whether this population is a feature of long COVID, which results in some people having a reduced capacity to fight off the symptoms of COVID infection long after the virus has dissipated.
Colourised transmission electron micrograph of hepatitis B virus particles (colourised red and yellow). Credit: NIAID and CDC (Transmission electron micrograph image courtesy of CDC; colourisation by NIAID).
Over 12 million people worldwide suffer from a chronic infection with the hepatitis D virus. This most severe viral liver disease is associated with a high risk of dying from liver cirrhosis and liver cancer. It is caused by the hepatitis D virus (HDV), which uses the surface proteins of the hepatitis B virus (HBV) as a vehicle to specifically enter liver cells via a protein in the cell membrane – the bile salt transporter protein NTCP. This cell entry can be prevented by the active agent bulevirtide.
An international research team has now succeeded in deciphering the molecular structure of bulevirtide in complex with the HBV/HDV receptor NTCP at the molecular level. The research results published in the journal Nature Communications pave the way for more targeted and effective treatments for millions of people chronically infected with HBV/HDV.
The entry inhibitor bulevirtide is the first and currently only approved drug (under the drug name Hepcludex) for the treatment of chronic infections with the hepatitis D virus. The active agent effectively inhibits the replication of hepatitis D viruses and leads to a significant improvement in liver function. But the exact mechanism by which bulevirtide interacts with the virus entry receptor on the surface of the liver cells – the bile salt transporter protein NTCP (sodium taurocholate cotransporting polypeptide) – and thereby inhibits the entry of the viruses into the cells was previously unknown.
In order to understand the molecular interaction of bulevirtide and NTCP at the molecular level, the researchers first generated an antibody fragment that specifically recognises the NTCP-bulevirtide complex and makes it accessible for analysis when bound to nanoparticles. This complex was then analysed using cryo-electron microscopy, which allowed to visualise structural details with atomic resolution. The research results represent a milestone in understanding both the interaction of HBV and HDV with their cellular entry receptor NTCP and the mechanism of cell receptor blockade by bulevirtide.
How bulevirtide blocks the cell entry receptor NTCP
The analysis showed that bulevirtide forms three functional domains in the interaction with the HBV/HDV receptor NTCP: a myristoyl group that interacts with the cell membrane on the outside of the cell; an essential core sequence (‘plug’) that fits precisely into the bile salt transport tunnel of the NTCP like the bit of a key into a lock; and an amino acid chain that stretches across the extracellular surface of the receptor, enclosing it like a brace.
“The formation of a ‘plug’ in the transport tunnel and the associated inactivation of the bile salt transporter is so far unique among all known virus-receptor complexes. This structure explains why the physiological function of the NTCP is inhibited when patients are treated with bulevirtide,” says Prof Stephan Urban, DZIF Professor of Translational Virology and Deputy Coordinator of the DZIF research area Hepatitis, in whose laboratory at Heidelberg University the active agent bulevirtide was developed.
“Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents – so-called peptidomimetics – with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration,” adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen.
Evolutionary adaptation of hepatitis B viruses to host species
The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV.
“Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs,” adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen.
“Thanks to the structural details of the interaction with bulevirtide, we have also gained insights that enable the development of smaller active agents — so-called peptidomimetics — with improved pharmacological properties. Our structural analysis also lays the foundation for the development of drugs that are not only based on peptides and possibly enable oral administration,” adds the co-author of the study, Prof Joachim Geyer from the Institute of Pharmacology and Toxicology at Justus Liebig University Giessen.
Evolutionary adaptation of hepatitis B viruses to host species
The structural analysis also helped to decode an important factor in the species specificity of hepatitis B and D viruses. According to the findings of the analysis, the amino acid at position 158 of the NTCP amino acid chain plays an essential role in virus-receptor interaction. A change in the amino acid at this position prevents the binding of HBV/HDV. This explains why certain Old World monkeys, such as macaques, cannot be infected by HBV/HDV.
“Our findings enable a deeper understanding of the evolutionary adaptation of human and animal hepatitis B viruses to their hosts and also provide an important molecular basis for the development of new and targeted drugs,” adds co-author Prof Dieter Glebe, DZIF scientist at the Institute of Medical Virology at Justus Liebig University Giessen.
Researchers from Rutgers University in the U.S. believe that they are ahead in a race to find an oral COVID-19 treatment to supplement or replace the antiviral Paxlovid. Their report, published in Science, shows that an alternative medication, a viral papain-like protease inhibitor, inhibits disease progression in animals while also possessing an important advantage over Paxlovid – fewer prescription drug contraindications.
“COVID-19 remains the nation’s third leading cause of death, so there’s already a massive need for additional treatment options,” said Jun Wang, senior author of the study and associate professor at Rutgers. “That need will grow more urgent when, inevitably, COVID-19 mutates in ways that prevent Paxlovid from working.”
The Rutgers team hoped to make a drug that interfered with viral papain-like protease (PLpro), a protein that performs important functions in all known strains of COVID-19.
Creating such a drug required detailed information about PLpro’s structure, which Wang’s team got from the Arnold Lab at Rutgers’ Center for Advanced Biotechnology and Medicine (CABM).
Precise knowledge of PLpro’s structure enabled Wang’s team to design and synthesise 85 drug candidates that would bond to – and interfere with – this vital protein.
“The PLpro crystal structures showed an unexpected arrangement of how the drug candidate molecules bind to its protein target, leading to innovative design ideas implemented by professor Wang’s medicinal chemistry team,” said Eddy Arnold, who is a professor at CABM.
Laboratory testing established that the most effective of those drug candidates, a compound dubbed Jun12682, inhibited several strains of the SARS-CoV-2 virus, including strains that resist treatment with Paxlovid.
Oral treatment with Jun12682 on SARS-CoV-2-infected mice was shown to reduce viral lung loads and lesions while improving survival rates.
“Our treatment was about as effective in mice as Paxlovid was in its initial animal tests,” said Wang, who added the experimental drug appears to have at least one major advantage over the older drug.
“Paxlovid interferes with many prescription medications, and most people who face the highest risk of severe COVID-19 take other prescription medicines, so it’s a real problem,” Wang said.
“We tested our candidate Jun12682 against major drug-metabolising enzymes and saw no evidence that it would interfere with other medications.”
A new study has identified potential broad-spectrum antiviral agents that can target multiple families of RNA viruses with pandemic potential. The study, published in Cell Reports Medicine, tested an array of innate immune agonists that work by targeting pathogen recognition receptors, and found several agents that showed promise, including one that exhibited potent antiviral activity against members of RNA viral families.
The authors say recent epidemics as well as global climate change and the continuously evolving nature of the RNA genome indicate that arboviruses, viruses spread by arthropods such as mosquitoes, are prime candidates for the next pandemic after COVID. These include Chikungunya virus (CHIKV), Dengue virus, West Nile virus and Zika virus. The researchers write: “Given their already-demonstrated epidemic potential, finding effective broad-spectrum treatments against these viruses is of the utmost importance as they become potential agents for pandemics.”
Led by Gustavo Garcia Jr. in the UCLA Department of Molecular and Medical Pharmacology, researchers found that several antivirals inhibited these arboviruses to varying degrees. “The most potent and broad-spectrum antiviral agents identified in the study were cyclic dinucleotide (CDN) STING agonists, which also hold promise in triggering an immune defence against cancer,” said senior author Vaithi Arumugaswami, Associate Professor in the UCLA Department of Molecular and Medical Pharmacology.
“A robust host antiviral response induced by a single dose treatment of STING agonist cAIMP is effective in preventing and mitigating the debilitating viral arthritis caused by Chikungunya virus in a mouse model. This is a very promising treatment modality as Chikungunya virus-affected individuals suffer from viral arthritis years and decades from the initial infection,” Arumugaswami added.
“At molecular level, CHIKV contributes to robust transcriptional (and chemical) imbalances in infected skin cells (fibroblasts) compared to West Nile Virus and ZIKA Virus, reflecting a possible difference in the viral-mediated injury (disease pathogenesis) mechanisms by viruses belonging to different families despite all being mosquito-borne viruses,” said senior author Arunachalam Ramaiah, Senior Scientist in the City of Milwaukee Health Department.
“The study of transcriptional changes in host cells reveals that cAIMP treatment rescues (reverses) cells from the harmful effect of CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways,” Ramaiah added.
The study concludes that the STING agonists exhibited broad-spectrum antiviral activity against both arthropod-borne- and respiratory viruses, including treaded SARS-CoV-2 and Enterovirus D68 in cell culture models.
Garcia notes, “The next step is to develop these broad-spectrum antivirals in combination with other existing antivirals and be made readily available in the event of future respiratory and arboviral disease outbreaks.”
Colourised transmission electron micrograph of monkeypox virus particles (green) cultivated and purified from cell culture. Credit: NIAID
In light of the recent spread of monkeypox virus, now declared a public health emergency of international concern by the World Health Organization, there is a need for treatments. In an article published in Clinical Infectious Diseases, authors review three antiviral agents with activity against monkeypox: cidofovir, brincidofovir, and tecovirimat.
Human monkeypox, caused by the monkeypox virus, a member of the genus Orthopoxvirus within the Poxviridae family of double-stranded DNA (dsDNA) viruses, was first described in a baby in the Democratic Republic of Congo in 1970. Since then, it has resulted in multiple outbreaks in Central and West Africa, and occasionally in Europe and North America. Human-to-human transmission in households has been reported, especially among those unvaccinated against smallpox.
Cidofovir Although cidofovir has broad activity against many DNA viruses including orthopoxviruses, it is only FDA approved for the treatment of cytomegalovirus retinitis. Cidofovir (CDV) is a prodrug, which must first enter host cells, where it is converted into the active form, CDV diphosphate (CDV-pp). CDV-pp has a prolonged intracellular half-life, and slows viral DNA replication by being incorporated into the growing DNA strand. Pharmokinetics suggest poor oral absorption and is available as intravenous infusions.
In humans, CDV has been used to treat ocular cowpox and as a topical treatment for molluscum cantiogosum.
Brincidofovir Brincidofovir (BCV) is a lipid-conjugated CDV analogue, FDA-approved in 2021 for the treatment of smallpox. Like CDV, BCV has broad activity against dsDNA viruses. It can be be taken up by the small intestines, and unlike CDV, which slowly crosses cellular membranes, brincidofovir readily enters host cells due to its lipophilicity. Inside cells, BCV is converted into CDV and then CDV-pp. CDV-pp reaches higher intracellular concentrations after BCV administration due to its ability to cross cellular membranes more efficiently. Like CDV, BCV has a prolonged intracellular half-life and inhibits viral replication.
In prairie dog models, which exhibit similarity to the human course, BCV improved survival when administered shortly after infection, suggesting that early treatment is important.
Tecovirimat Tecovirimat was FDA approved in 2018 for the treatment of smallpox, and has activity against orthopoxviruses, but has no notable activity against other dsDNA viruses. Tecovirimat targets a gene which encodes for membrane protein p37, responsible for the formation of extracellular enveloped virus.
The oral route results in better absorption for tecovirimat, and is effective against monkeypox virus in macaques and prairie dogs. Administration within 72 hours of exposure to poxvirus reduced lesion severity and mortality in various animal models.
Tecovirimat synergises with BCV, and was successfully used to treat monkeypox in two human cases.
Conclusion The authors note that while CDV and BCV inhibit DNA replication, tecovirimat is more specific to orthopoxviruses and prevents enveloped virus formation, stalling cell-cell transmission.
BCV and tecovirimat could be promising therapeutic candidates based on their tolerability profiles, they conclude. More studies are needed to identify those most at risk from monkeypox and establish the optimal initiation time and duration for therapy.
Interim analysis of a South African clinical trial has revealed that nitazoxanide, an oral antiparasitic agent with antiviral properties, was ineffective in improving outcomes in ambulatory patients with mild-to-moderate COVID.
Funded by the South African Medical Research Council (SAMRC), the study was performed at four sites in South Africa. The primary goal of the trial was to evaluate the effectiveness of nitazoxanide (1g twice daily for 7 days) in reducing the progression from mild to severe COVID in ambulatory patients. Progression to severe disease was defined as hospitalisation or death. The trial underwent an interim analysis at 67% of the recruitment target (290 participants), and the data was reviewed by an independent data and safety monitoring board (DSMB). Following the interim analysis, the DSMB recommended halting recruitment of the trial on the grounds of futility.
No significant difference was seen in serious adverse events, which included all causes of hospitalisation and death, between the nitazoxanide and the placebo groups [12/144 (8.3%) vs 10/146 (6.8%)]. Hospitalisation and death specifically due to COVID showed the same pattern [7/144 (4.9%) vs 8/146 (5.5%)].
Principal investigator Prof Keertan Dheda from the University of Cape Town (UCT) and the London School of Hygiene and Tropical Medicine, said that the results of the trial, although disappointing, contributes to the growing body of evidence, clarifying what works and what doesn’t for the treatment of COVID. Thus, clarifying what does not work is as important as finding effective therapies so that clinically useful management algorithms can be developed.
Nitazoxanide is a low-cost broad-spectrum antiviral drug with an extensive safety record. Originally developed as antiparasitic, it seemed promising against SARS-CoV-2 in the lab but the real world test did not show any benefit. It is still possible that nitazoxanide may be of benefit at higher doses (greater than the dose used in the trial, which was already twice the normal dose), however this will most likely cause an increase in intolerable gastrointestinal side effects. “The next step will be to focus on formally publishing the data in a peer reviewed journal and to evaluate secondary objectives of the study, including assessing the efficacy of nitazoxanide in reducing the duration of illness, reducing SARS-CoV-2 viral load, and its efficacy, if any, in preventing COVID in close contacts,” said Prof Dheda.
Prof Dheda concluded that nitazoxanide could have a less than 30% benefit which may be detectable in a larger study. However, it is questionable whether such an effect size is clinically relevant given the number needed to treat to prevent disease progression, adverse events, cost and that other therapies have emerged (eg paxlovid) with an efficacy benefit of greater than 80%.
SAMRC President and CEO, Prof Glenda Gray said although the study did not meet its primary endpoint, the results are an important addition into the scientific repository. “COVID and HIV in their very nature are unique and complex viruses which have posed unprecedented challenges for vaccine development, globally – however, the knowledge gained from this trial will help us advance our pursuit of effective therapies and vaccines for both COVID and HIV alike,” said Prof Gray.
Prof Gray, who also has led numerous trials in search of effective HIV and COVID vaccines, said COVID poses substantial challenges for those living with HIV which evades the immune system. “Until an effective vaccine has been found, all people living with HIV should take all recommended preventive measures to minimise their exposure to COVID,” concluded Prof Gray.
Researchers have developed a new nanoparticle combination as a broad-spectrum anti-RNA virus treatment.
The results of their study have been published on the bioRxiv preprint server. Note that as a preprint, this paper has not yet been peer reviewed. Non-specific antivirals offer a number of attractive advantages. Their broad spectrum activity suppresses mutations, and would they also readily be at hand for future outbreaks. Nanoparticles are one possibility, with reduced toxicity.
Silver nanoparticles (AgNPs) are well-established as antibacterial and antiviral agents, and are the subject of many exotic biomedical applications. The mechanism of AgNPs is thought to be through physiochemical destruction of the microbial surface, with internal disruption from free Ag+ ions and reactive oxide species. Graphene oxide (GO) also has anti microbial properties. With its high surface area, GO also acts as a drug carrier.
The researchers produced seven different material combinations using three different methods: reduction with silver salt, direct addition of Ag nanospheres, and direct addition of Ag nanospheres to thiolised graphene. To test the materials against seasonal-type infections as well as the kind of virus that could be expected from a future pandemic, the researchers tested the nanoparticles with influenza A virus (IAV) and human coronavirus (HCoV) OC43. IAV is an enveloped virus of the orthomyxovirus family with a segmented single-stranded RNA genome; it causes flu pandemics. HCoV-OC43 is an enveloped betacoronavirus with a single-stranded RNA genome associated with the common cold in humans.
Two of the GO-AgNP materials showed rapid, potent antiviral activity in solution against the viruses. The remaining five materials possessed a range of modest to no antiviral effects against IAV, the researchers reported. They observed a synergistic effect between the AgNPs and GO, with mechanism of action possibly being rapid disruption of the viral envelope. With high levels of antiviral agents, the combination of AgNPs with GO was found to show greater antiviral performance and lower toxicity.
“Our finding that graphene oxide/silver nanoparticle ink can rapidly prevent in vitro infection with two different viruses is exciting, and suggests that the ink has the potential to be used in a variety of applications to help reduce the spread of viruses in the environment,” said co-author Dr Meredith J Crane.
Journal information: Graphene oxide/silver nanoparticle ink formulations rapidly inhibit influenza A virus and OC43 coronavirus infection in vitro, Meredith J. Crane, Stephen Devine, Amanda M. Jamieson, bioRxiv 2021.02.25.43
