Investigational drug ameliorates neuronal DNA damage and inflammation in Alzheimer's model

The pKa for an amino acid is an acid dissociation constant that refers to the equilibrium between the protonated and deprotonated forms of the backbone amino group, backbone carboxyl group, and any potential acid/base component of the variable group. The net charge of the protein is determined by summing the charge of individual amino acids across the protein. pKa relates to the equilibrium constant and defines the transition between two structural forms of an amino acid–protonated and deprotonated. Amino acids possess distinct pKas for the carbonyl group, amino group, and any functional groups on the side chain that may be protonated or deprotonated. There is always one more structure than the number of pKa values for amino acids. For example, if there were two pKa values, three structures can be discerned. This is illustrated below using glycine, which has two pKa values – pKa 1 represents the (de)protonation of the carboxyl group and pKa2 represents the (de)protonation of the amine group: When the pH< pKa protonation of the amino and carboxyl groups occurs, resulting in a net +1 positive charge for glycine. When the pH is increased to a value between the two pKas(pKa2>pH> pKa1), the carboxyl group is deprotonated while the amino group remains protonated. This represents the zwitterionic form of the amino acid as it simultaneously possesses a positive and negative charge. When the pH> pKa2, the amino group is deprotonated and loses its charge. The amino acid now carries a net negative charge of -1. The zwitterionic form of the amino acid can exist at any pH value between pKa1 and pKa2.

Stupp's team is currently testing these systems in animal studies and adding additional signals to create highly bioactive therapies. "With the success of the study in human cartilage cells, we predict that cartilage regeneration will be greatly enhanced when used in highly translational pre-clinical models," Stupp said. "It should develop into a novel bioactive material for regeneration of cartilage tissue in joints." Stupp's lab is also testing the ability of dancing molecules to regenerate bone - and already has promising early results, which likely will be published later this year. Simultaneously, he is testing the molecules in human organoids to accelerate the process of discovering and optimizing therapeutic materials. Stupp's team also continues to build its case to the Food and Drug Administration, aiming to gain approval for clinical trials to test the therapy for spinal cord repair. "We are beginning to see the tremendous breadth of conditions that this fundamental discovery on 'dancing molecules' could apply to," Stupp said. "Controlling supramolecular motion through chemical design appears to be a powerful tool to increase efficacy for a range of regenerative therapies." The study, "Supramolecular motion enables chondrogenic bioactivity of a cyclic peptide mimetic of transforming growth factor-β1," was supported by a gift from Mike and Mary Sue Shannon to Northwestern University for research on musculoskeletal regeneration at the Center for Regenerative Nanomedicine of the Simpson Querrey Institute for BioNanotechnology. Yuan, S. C., et al. (2024). Supramolecular Motion Enables Chondrogenic Bioactivity of a Cyclic Peptide Mimetic of Transforming Growth Factor-β1. Journal of the American Chemical Society. doi.org/10.1021/jacs.4c05170

These peptides, like the parent compound AC253, acted as antagonists at the AMY receptor. They were also resistant to protein breakdown, and crossed the blood-brain barrier easily when injected into the abdominal cavity, to localize in the hippocampus, which is crucial in memory. These peptides protected the brain against beta-amyloid injury, and normalized the AD-associated impairment of the memory-associated long-term potentiation of nerve impulses in the hippocampus. They improved memory testing results, and reduced the level of inflammation in the brain. These effects appear to be mediated via the blockade of AMY receptors. For instance, inhibition of microglial AMY receptors reduce the activation of the inflammasome NLRP3. This reduces the secretion of inflammatory chemicals in the surrounding brain tissue, which offers another mechanism for lower amyloid production. In addition, these peptides increase the rate of outflow of amyloid beta from the brain, which also contributes to a lower level of amyloid after treatment. These marked changes all occurred within a relatively short span of treatment. A very important additional finding was that treatment with these peptides brought about improvement in mice which were showing signs of well-established AD in the brain as well as in their behavior. This is unique in that most therapies fail to affect the progress of AD once it has begun to manifest clinically. Peptides also have fewer off-target effects. Small molecules are easy to administer, inexpensive to make and cross the blood-brain barrier more rapidly. For this reason, the team resorted to computational tools and artificial intelligence to come up with a new small molecular drug based on these peptides. This can be taken orally, and is similar in size and structure to the medications used for medical conditions like high blood pressure. An optimized version is being developed to enable human trials to be conducted. The work so far has taken about two decades, building step upon painstaking step to come up with the right solution. However, says Jhamandas, “Occasionally you come across a discovery that has the potential to change the game in a very fundamental way, like hitting a home run, and I'm very excited that we are really on to something here.” Short amylin receptor antagonist peptides improve memory deficits in Alzheimer’s disease mouse model. Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang & Jack Jhamandas. Scientific Reports, volume 9, Article number: 10942 (2019). https://doi.org/10.1038/s41598-019-47255-9. https://www.nature.com/articles/s41598-019-47255-9

In a typical neuron, the cell body comprises only about 10-20% of the cytoplasm; the rest lies in the axon and dendrites. Thus, understanding neurons requires acknowledging the axon's role. We advocate for the research focus to consider this polarization and complex structure. By highlighting different transcriptomics within axons versus cell bodies and targeting their regulation, we can influence the entire neuron's functioning, potentially transforming treatment approaches.

This is a win for the field. Until now, we have been focused on immune therapies that might make tumors more vulnerable to the body's immune system, and on finding new chemotherapy combinations that kill cancer cells. This new treatment has given us a new focus, and I think it will spur a lot of scientific discovery over the next few years. There have only been a handful of KRAS researchers and their relevance to therapy was always questioned. That is about to change. The most important next step for the field is to better understand the biology of cancer. We know that many pancreatic tumors will eventually become resistant to daraxonrasib, and we need to understand how this happens. We also need to identify additional genetic pathways and treatments that can target them. That's how we will turn pancreas cancer from a deadly, deadly cancer into something we can manage-and one day, even cure.