Brazilian researchers who study native poisonous fish have paved the way for the development of drugs for the treatment of infectious breast diseases such as multiple sclerosis and asthma.
The toxic toad Thalassophryne nattereri contains a peptide (TnP) with anti-inflammatory and anti-allergic ability. Proof of this ability has now come through the zebrafish Danio rerio, a popular aquarium species native to South Asia that shares 70% of its genome with humans and is widely used as a model for in vivo testing in drug development.
The researchers tested TnP in D. rerio to quantify its toxicity. In just over a year, their research showed that the peptide is safe. He did not cause heart problems or brain problems in the toxic tests they performed.
The study was conducted at the special laboratory of the Butantan Institute for Applied Toxinology in São Paulo (Brazil) by researchers affiliated with the Center for Research on Toxins, Immune Response and Cell Signaling (CeTICS), one of the Centers Research, Innovation and Distribution (RIDCs). funded by the São Paulo Research Foundation – FAPESP.
In addition to confirming the safety of peptide when used as an anti-inflammatory agent, the results confirm the importance of D. rerio as another animal model for drug development that saves time and money.
Preclinical tests are important to determine molecular efficacy (therapeutic activity) in vivo and to evaluate adverse effects and safety. In drug detection, 98% of fertilizers tested in animals are abandoned prior to clinical trials.
In an article published in Toxicology reports, the researchers claim that peptides represent about 2% of the global drug market but nonetheless they account for a market share worth around 20 billion USD.
“The results highlight a broad therapeutic index for TnP with non-lethal and safe doses from 1 nm [nanometer] to 10 μm [micrometer], without causing neurotoxicity or cardiotoxic effects. Low frequency of disorders [caused] with TnP it was associated with the high safety of the molecule and the ability of the developing embryo to process and destroy it. TnP crossed the blood-brain barrier without disturbing the normal architecture of forebrain, midbrain, and hindbrain [the three main developmental divisions of the brain], “the authors write.
The study came as a result of the study of master João Batista-Filho, led by Mônica Lopes Ferreira and Carla Lima da Silva. It used the Zebrafish Platform, launched in 2015 by CeTICS (read more at: agencia.fapesp.br/22156/).
The Zebrafish Platform is available to scientists for research, offering courses on zebrafish management and biology, and disseminating science. More than 160 researchers at 100 private and public institutions are currently collaborating through Zebrafish Network, also created by CeTiCS.
Science dies without investment and FAPESP’s commitment to this platform is now bearing fruit. Advanced research is being conducted here, along with preclinical trials that are important to both academia and industry. “
Mônica Lopes Ferreira, Director
Zebrafish has been used for decades in experiments conducted in other countries, she said, adding that Brazil is closing the gap and the animal’s rapid life cycle is speeding up the research process. .
The freshwater species is easy to manage, reproduces quickly, develops from egg to larva in 48-72 hours, and reaches adulthood at just three months of age. Zebrafish embryos are prominent and the effect of fertilizers on the organs of the animal can be easily seen, for example.
History
Ferreira and colleagues discovered TnP (T. nattereri peptide) in 2007. Meanwhile, Lima had performed routine laboratory tests to assess multiple sclerosis in rodents. The two researchers decided to work together to test the effectiveness of TnP in the treatment of the disease, concluding for its anti-inflammatory and immunomodulatory functions.
The TnP family consists of synthetic peptides containing a series of 13 L-amino-acids in their main structure. Synthetic products derived from TnP have been patented in at least nine countries including the US, India and Japan, as well as the EU. In Brazil, a patent application was filed in partnership with the pharmaceutical company Cristália.
Studies conducted by the group with mice between 2013 and 2015 had already shown that TnP can treat multiple sclerosis, delay the onset of severe symptoms and improve clinical signs of the disease.
Multiple sclerosis is a malignant autoimmune inflammatory disorder of the central nervous system, in which the immune system attacks the myelin sheath which protects neural fibers in the brain, spine and optic nerves, causing disturbances. on communication with the rest of the organism. It can cause muscle weakness, loss of vision, pain, and impaired motor coordination. It affects some 2.5 million people worldwide, including about 35,000 in Brazil, according to the Association for Multiple Sclerosis Association (ABEM).
Safety
In the article published in Toxicology reports, the researchers say, drug – induced cardiotoxicity is the main reason for removing drugs from the market. “For example, between 1994 and 2006, 45% of discontinued medications such as cardiac ischemia and arhythmogenesis had adverse effects. In this line zebrafish has emerged as an organic model for cardiovascular study, studying function gene and modulating a combination of human disease side-effects of chemotherapeutic drugs or specifically on screening drug candidates, ”they note.
For Batista-Filho, the study provides further evidence for the value of the zebrafish model in preclinical research. “It will not replace mice, but it will avoid future costs on molecules that are not promising or are too toxic in previous stages,” he said when asked about preservation regarding the use of zebrafish in their tests compared to rodents.
Claiming to invest in science and research in Brazil, Batista-Filho said he was thrilled to complete the publication of his master’s dissertation in a scientific journal. “I’m delighted,” he said. “Publishing is a milestone for any scientist. You focus on the good that research can do, but publishing is a recognition of the team’s hard work.”
Source:
Fundação de Amparo à Pesquisa do Estado de São Paulo
Magazine Reference:
Batista-Filho, J., et al. (2021) Early preclinical screening using zebrafish (Danio rerio) demonstrates the safety of the anti-inflammatory therapeutic candidate TnP. Toxicology reports. doi.org/10.1016/j.toxrep.2020.12.004.