Nasal spray shows promise in combating Alzheimer's

The aim of these experiments was twofold. First, Dr. Mills at MDACC wanted to confirm that COTI-2 was preferentially killing cancer cells with p53 mutations. Secondly he wanted to identify the range of different mutations in the p53 gene that were responsive to COTI-2.

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.

Leucine and isoleucine are transported into organs (including the brain) by the use of L1-neutral amino acid transporter, or LAT1. As other amino acids are also transported by LAT1, leucine and isoleucine must compete for a binding site. Amino acids imported into the brain can be used to synthesize neurotransmitters, therefore changes in amino acid concentrations may have an effect on the neurotransmitters that are made. Leucine has additional roles; it may inhibit breakdown of muscle, causes the secretion of insulin from pancreatic β-cells, as well as modulate food intake regulation through its action on the central nervous system.

Excess carbohydrates in the diet are converted into triglycerides, which involves the synthesis of fatty acids from acetyl-CoA in a process known as lipogenesis, and takes place in the endoplasmic reticulum. In animals and fungi, a single multi-functional protein handles most of these processes, while bacteria utilize multiple separate enzymes. Some types of unsaturated fatty acids cannot be synthesized in mammalian cells, and so must be consumed as part of the diet, such as omega-3. Acetyl-CoA is also involved in the mevalonate pathway, responsible for producing a wide range of isoprenoids, which include important lipids such as cholesterol and steroid hormones.

The tools we are building and applying at ApconiX are currently internal-facing, supporting our scientists and collaborators in delivering thoroughly researched, evidence-based, and authoritative toxicology information in a timely manner. Even though I did not directly interact with ApconiX while I was at Redx, my experience in biopharma strongly shapes how I think about usability. At ApconiX, we constantly consider how others will interpret and use the data and insights we generate. For example, our early SAR work around seizure liability has identified preliminary relationships between chemical substructural patterns and seizure risk. Although this work is in its infancy, these are the kinds of insights that discovery chemists could interpret directly and apply from day one to help mitigate risk. For target safety assessments, the ApconiX data science team have collated a large data sets including our Acuity expression atlas for expression data, enabling our data scientists and bioinformaticians to generate highly informative, data-driven insights and visualizations. By leveraging AI tools, such as LLM workflows and agents, we can efficiently support consistent and thorough analyses, making safety information more accessible and actionable.