2024-01-21 17:00:36
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A dengue station in Bangladesh. The disease is caused by a flavivirus. Habibur Rahman /DNDi © IMAGO/aal.photo
To be better prepared for the next pandemic, research teams are working on developing drugs with broad effectiveness
Frankfurt – The next pandemic will come, that is almost certain among experts. However, it is questionable when and which pathogen will cause it. Many experts suspect that, as with the Spanish flu and Covid-19, a virus will be the trigger and that the greatest danger comes from a zoonosis, an infectious disease that has spread from an animal to humans.
“Viruses are the most common species on earth,” says virologist and cell biologist Ralf Bartenschlager from the Center for Infectious Diseases at Heidelberg University and the German Cancer Research Center in Heidelberg. “We can assume that hundreds of thousands of unknown virus types exist. And for the vast majority, we have no treatment should one of these viruses cause an epidemic or pandemic, while for an emerging bacterium there is still hope that it will respond to one or another antibiotic.”
Research teams want to develop antiviral drugs with broad effectiveness
A number of research teams are therefore working on the development of antiviral drugs with broad effectiveness. These should not only inhibit a specific type of virus, as is the case with most antiviral drugs, but should also be active against many different types of viruses at the same time. This would make us better prepared for a future pandemic caused by a previously unknown virus, similar to broad-spectrum antibiotics for bacterial infections.
Ralf Bartenschlager is one of the scientists looking for broad-spectrum antivirals. The specialist in RNA viruses heads the “Nucleoside Booster Project” of the German Center for Infection Research (DZIF) and the research organization “Drugs for Neglected Diseases initiative” (DNDi). The focus of the search is on nucleoside analogues that target polymerases – certain enzymes. Nucleosides are building blocks of the nucleic acids DNA and RNA, which carry genetic information. They consist of one of the four bases adenine, guanine, cytosine and thymine (or uracil in the case of RNA) as well as a sugar molecule. When the genetic information is replicated, the nucleosides are strung together using polymerases, creating new DNA or RNA copies.
Current research project is working on antivirals
For nucleoside analogues, the chemical composition is modified with the aim of disrupting the process of replication of genetic information. “Nucleoside analogues ensure that the assembly line in the cell is stopped and new virus genomes are no longer produced,” explains Bartenschlager: “And the special thing: polymerases are inside the cell, where the nucleosides are recognized and strung together , quite constant, even between distantly related viruses. This gives us the chance that nucleoside analogues have a broad-spectrum effect.”
Ralf Bartenschlager is a virologist and cell biologist at the Center for Infection Research at Heidelberg University. © Philip Benjamin
For the current research project, 150 different nucleoside analogues were produced and sent to several German high-security laboratories by the German Center for Infection Research in Braunschweig. There, researchers will examine the substances for their effectiveness against types of viruses that are listed as particularly dangerous by the World Health Organization (WHO) because they have a high risk of transmission from animals to humans.
In practice it looks like this: one laboratory tests against the Ebola virus, in another against the Crimean-Congo fever virus, in the next against the Lassa virus and so on. Bartenschlager and his team are concentrating on effectiveness against flaviviruses, which cause dengue fever, Zika, West Nile fever and Japanese encephalitis, among others. All results should be made public quickly worldwide in order to initiate further research and development.
Nucleoside analogues are used in cancer therapy
Nucleoside analogues are nothing new in medicine; they have been used since the 1950s as cytostatics in cancer therapy, for example against leukemia. Some drugs that suppress the immune system are also nucleoside analogs. But viruses are also already being combated on this basis, including hepatitis B and C as well as infections with HIV, herpes, hantaviruses and adenoviruses. However, these nucleoside analogues are “designed so that they only work with a high level of specificity against one pathogen,” explains Bartenschlager.
Nucleoside analogues have also already been approved for the treatment of Covid. The first is Remdesivir, which was originally developed to treat Ebola and Marburg fever, but was not sufficiently effective against these diseases. Even with Corona, the success was not resounding. According to Bartenschlager, there are several reasons for this: “Remdesivir does not have good biological availability. And it has to be given intravenously, which is unfavorable in the case of a highly contagious disease where you can transmit a virus before you have symptoms. Because no one would come up with the idea of administering a drug intravenously as a prophylactic if you don’t even know whether the disease will break out.” In Covid patients in the intensive care unit, the amount of virus is already so low when the disease is advanced that antiviral therapy hardly helps be achieved.
According to the virologist, future therapeutics based on nucleoside analogues would therefore have to be taken as tablets or administered as a spray. “Everything else could be forgotten during a pandemic outbreak.”
The cooperation
Die Drugs for Neglected Diseases Initiative (DNDi) is a non-profit research organization. Its goal is to develop and provide safe and affordable treatments for neglected diseases that primarily affect people in poor countries, often in the tropics. The initiative was founded in 2003 by Doctors Without Borders and health facilities in countries where neglected tropical diseases are endemic. Since its founding, DNDi researchers have developed twelve new therapies for six deadly diseases, including sleeping sickness and leishmaniasis.
The German Center for Infection Research (DZIF) is a research association founded in 2012. More than 500 doctors and scientists from 35 participating research institutions at seven locations are working on new methods for diagnostics and protection against infectious diseases and their therapy. These include HIV/AIDS, malaria, hepatitis, tuberculosis, gastrointestinal infections, neglected tropical diseases and emerging zoonoses. Another focus is resistant bacteria. (pam)
Molnupiravir is supposed to paralyze viruses through mutations
The second Covid drug based on a nucleoside analogue is molnupiravir. Unlike the substances that the researchers are currently working on, it is not intended to interrupt the replication of genetic information, but rather to cause so many mutations in the newly created viral genomes that they are no longer functional. However, according to Bartenschlager, this appears to “promote the emergence of new virus variants” and it could increase the risk of genetic changes in human cells as well. Molnupiravir is not approved in the EU due to lack of sufficient clinical efficacy.
Corona remains an issue in the current research project. Specifically, scientists want to develop a nucleoside analogue that is effective against the known human coronaviruses, but also against many from the animal kingdom – in the hope that this will also cover a possible emerging pathogen from this family of viruses.
Bartenschlager does not see relying solely on protection through vaccinations as an option in the future. “You always need both, vaccination and therapeutic agent. Because there will always be people who either don’t respond to a vaccination, react very poorly, or don’t get vaccinated at all.” In addition, the immune response on the mucous membranes is often not so good with viruses that infect the respiratory tract.
Nucleoside analogues could theoretically have a mutagenic effect
No medication is without side effects. What might be expected with nucleoside analogues against viral polymerases? Bartenschlager sees a theoretical risk that they can have a mutagenic effect; another is “a certain toxicity”. “But these medications are only given for a relatively short period of time, four to five days, because it is not about chronic infections but about acute infections. That’s why I think you can live with such effects within certain limits.”
In any case, researchers still have a long way to go. Because even if substances with good effectiveness are found in the laboratory, it does not mean that it works the same way in the living organism. In addition, the production of nucleoside analogues is a “highly complicated process” and requires special chemical expertise, says Bartenschlager. “Even if we find something, it can be expected that it will still take several years until it is clinically available. That’s why you shouldn’t wait until the next pandemic to develop it.” And then there’s the issue of financing. The aim is to convince potential donors to invest in a drug “of which we do not yet know for sure whether and when and to what extent we will need it in the future”. (Pamela Dörhöfer)
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