Novel peptide PEPITEM shows promise in fighting 'inflammaging'

It is one of the largest gathering of analytical and other scientists, and yet, all the presentations are in a relatively localized area, so one can easily access a greater variety of topics and scientists in a limited amount of time. It is also one of the biggest exhibitions in the world, and having this exhibition can provide useful technical information, often unknown or unexplained in academic talks. I bring a significant number of students to Pittcon. They must give a talk or poster in order to attend. I think this is really important as it is good for them. They love the whole experience, from the networking, giving their presentations, being exposed to new topics, new parts of the country. A lot of them have not traveled so it is a wonderful opportunity. That is why we always bring as many students as we can and have them participate; they love it.

The study began with a bowl of mouse chow. Rather than start piecewise, one food after another, the researchers screened regulatory T cells from mice given a normal diet. They looked for what the regulatory T cells were attaching to, then mapped them backward to specific parts of the chow. They found three proteins-more specifically, they found small, specific bits of those proteins called epitopes-that the regulatory T cells recognized. The epitopes were found in three different food proteins: one from corn, one from wheat, and one from soybean. Notably, all three epitopes are from seed proteins, suggesting that these highly abundant plant proteins are commonly recognized by the immune system's tolerance mechanisms. Furthermore, the most abundant T cells were those reactive to the corn epitope, which makes sense given that corn is not a common allergy. Soy, on the other hand, is one of the major allergies in humans, so the identification of a soybean epitope is especially exciting, notes Blum. Additionally, the mammalian receptor that interacts with the identified soybean epitope also interacts with sesame, helping explain cross-tolerance, or when a tolerance to one food infers a tolerance to another. With the new epitopes identified, the researchers had a few follow-up questions, like where do these regulatory T cells live? And how do they perform in an inflamed versus a healthy environment? They used mice and cell culture models to answer these questions, finding that the regulatory T cells are primarily located in the gut and their activities vary based on whether they are in an inflamed or healthy environment, either working to reduce inflammation or sustain an absence of inflammation.

Reporting in the October 13 issue of Nature, a team from Denmark-based biotech company Novozymes, and researchers from Georgetown University Medical Center and the David Geffen School of Medicine at UCLA, say they have isolated "plectasin," the first defensin ever found in fungi. The research was performed at Novozymes laboratories in Denmark. Defensins are peptides, miniature protein molecules that are produced by a wide range of animals to protect themselves against infection. Humans have defensins in their white blood cells and in their skin, for example, but it is believed that this new fungal defensin, plectasin, is more potent and targets certain bacteria more specifically. Indeed, when plectasin was tested in the laboratory and in animals, it proved to be highly effective against the bacteria Streptococcus pneumoniae, and Streptococcus pyogenes, including strains that are now resistant to conventional antibiotics. These bacteria are responsible for such diseases as meningitis, community-acquired pneumonia, strep throat, life-threatening sepsis, and flesh destroying skin infections. The discovery of plectasin has implications for the development of defensins as a treatment against many common, and deadly, infections, and may initiate a new era of antibiotic discovery and development, said study co-author Michael Zasloff, M.D., Ph.D., Professor in the Departments of Surgery and Pediatrics at Georgetown University Medical Center. Zasloff says that the field of antibiotic development has not changed much since 1929 when Alexander Fleming realized that the fungal "bread mold" Penicillium, which had landed by chance in a Petri dish produced a substance that eliminated colonies of staphylococcal bacteria. "Most antibiotics used by humans are produced by fungi and certain soil bacteria," he said. "Using our existing tools of discovery, we have failed to uncover any new classes of antibiotics from these sources over the past decade. However, by utilizing a new genetic approach that allowed the team to discover plectasin, we now know that a whole class of antibiotics has been overlooked." "This finding (plectasin), and the existence of about 200,000 additional species of fungi, opens up a vast universe to explore for novel peptide antibiotics," said co-author Robert Lehrer, M.D., Distinguished Professor of Medicine at the David Geffen School of Medicine at UCLA. Plectasin, if proven safe and effective in humans, could be on the market by 2012, said Lehrer. Zasloff and Lehrer are known internationally as experts in antimicrobial peptides - the class of antibiotics that plectasin falls within - and in this study they collaborated with Novozymes, a Danish biotech company that led the research. Zasloff and Lehrer are the only two scientists from U.S. universities on the team of 20 researchers who co-authored the research paper. All life forms have to defend themselves against microbial invaders - bacteria, fungi, viruses - and to do this, they produce antimicrobial defensin peptides. In humans, defensins are made by specific white blood cells and immune cells that later engulf foreign invaders, and by the skin and mucous membranes, in order to kill microbes before they invade protective barriers. Researchers believe that fungi have a similar system of defense, especially since these plant-like organisms live off rotting matter, said Zasloff. "They must compete with other organisms, like bacteria and viruses, which also want to consume the same meal. In addition, they need to defend themselves from being eaten by the microbes which surround them." But he said no one had been able to find defensins in fungi using traditional research techniques, which involved growing fungi in liquid cultures and then testing the culture to see if it contained any antibiotic molecule. The research team instead used the latest genetic science to search for the defensins they thought fungi must have. Selecting the Pseudoplectania nigrella species of fungus may have been serendipitous, Lehrer said, but the Novozymes team used state-of-the-art biotechnology to intercept ,and interpret its genetic messages and exhibited tremendous skill in producing plectasin efficiently, economically, and in large amounts." "I started working on antimicrobial peptides over three decades ago, said Lehrer, and my laboratory first described human defensins in 1985. So, the discovery of plectasin makes me feel like a grandfather." Further examination revealed that this defensin, plectasin, resembles defensins found in spiders, scorpions, dragonflies and mussels - thus suggesting that the defensins found in insects, molluscs and fungi arose from a common ancestral gene, the researchers say. Based on this information, the scientists now believe that defensins appeared in living things more than a billion years ago. The investigators then turned to the National Center for Antimicrobials and Infection Control, the Danish equivalent of the U.S. Centers for Disease Control, to test plectasin in the laboratory for antimicrobial activity against a broad spectrum of bacteria. It showed potent activity against several species of Gram-positive bacteria, and was especially active against S. pneumoniae (the leading cause of pneumonia), including all known clinical strains and those that are now resistant to conventional antibiotics. "That is important because increasing bacterial resistance to conventional antibiotics threatens the future of many antibiotics in current use," Zasloff said. "In mouse studies, plectasin showed extremely low toxicity, and was as effective as vancomycin and penicillin in curing the animals of experimental peritonitis (inflammation of the lining of the abdominal cavity, which can be deadly) and pneumonia caused by S. pneumoniae, the researchers report. "Although the precise mechanism by which plectasin exerts its antimicrobial activity is still under investigation, it may work by a mechanism that is very different from traditional antibiotics, Zasloff said. "As a group, defensins exhibit activity against many types of bacteria, fungi, protozoa, and even viruses. It is entirely possible that fungal defensins will be discovered that could be developed against all of these human pathogens," Zasloff added.

Uncertainty and model limitations are critical in safety assessment. There is clearly greater potential for animal or human harm from an incorrect safety assessment than from making the wrong molecule in early discovery, although uncertainty matters in both contexts. It is important to distinguish different types of uncertainty. Aleatoric uncertainty reflects irreducible randomness in a task, while epistemic uncertainty is model-related, such as hallucinations or lack of knowledge. For LLM systems, we use multiple methods to measure consistency and we have built fact-checking approaches in which a separate LLM independently verifies the primary engine's outputs. For QSAR models, including our SAR work around seizure liability, we can use statistical metrics such as confidence intervals to quantify and communicate uncertainty. Understanding that uncertainty exists and communicating it in both safety and discovery is critical. Uncertainty metrics tell us where potential blind spots may exist in our modelling allowing us to take action to improve over time. This applies to both safety and discovery. The aim is not to pretend AI removes uncertainty, but to make uncertainty visible so scientists can make better-informed decisions. Download the Full PDF to Revisit James McDonagh's Insights on AI in Drug Safety Discovery

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