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SLAC to the Future: How Light Reveals Potential Breakthrough Biomedical Molecule

Researchers employed advanced X-ray spectroscopic techniques at SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), which allowed them to peer deeper into the chemical properties of nitroxide. Credit: Greg Stewart/SLAC National Accelerator Laboratory

SLAC researchers are developing a new, light-activated method to produce the molecule, nitroxide, which opens doors for future biomedical applications.

Unveiling the Potential of Nitroxide

Scientists from the Department of Energy’s SLAC National Accelerator Laboratory have gained valuable insights into producing nitroxide, a molecule with potential applications in the biomedical field. While nitric oxide (NO) has long been on researchers’ radar for its significant physiological effects, its lesser-known cousin, nitroxide (HNO), has remained largely unexplored.

Research Collaboration and Outcomes

The study, published recently in the Journal of the American Chemical Society, was born out of a joint endeavor between teams at SLAC’s Linac Coherent Light Source (LCLS) X-ray laser and Stanford Synchrotron Radiation Lightsource (SSRL).

Nitroxide has many of the same physiological effects of nitric oxide – such as its ability to fight germs, prevent blood clots, and relax and dilate blood vessels – with additional therapeutic properties, such as efficacy in treating heart failure, as well as more potent antioxidant activity and wound healing. However, it is not a chemically long-lived speciesA species is a group of living organisms that share a set of common characteristics and are able to breed and produce fertile offspring. The concept of a species is important in biology as it is used to classify and organize the diversity of life. There are different ways to define a species, but the most widely accepted one is the biological species concept, which defines a species as a group of organisms that can interbreed and produce viable offspring in nature. This definition is widely used in evolutionary biology and ecology to identify and classify living organisms.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>species so methods that enable its targeted delivery are key to future biomedical applications.

Challenges and Further Exploration

To address this challenge, the team focused on a unique molecule, an iron-nitrosyl complex (Fe-NO). Their research aimed to understand the intricate properties of the Fe-NO bond, both before and after light exposure, to navigate the complexities of nitroxide production. They discovered that by exposing this molecule to optical light, they could break its bond, potentially producing nitroxide.

“Although this research is fundamental in nature, the hope is that other researchers can take what we learn from this molecule and build therapeutic technologies off of it by optimizing similar molecules for medicine,” said SLAC scientist and collaborator Leland Gee. “The idea would be to get a molecule that releases HNO in the body where it is needed and shine light on it to release it for the therapeutic properties.”

One of the challenges the team faced was the ambiguous distribution of electrons between the iron atomAn atom is the smallest component of an element. It is made up of protons and neutrons within the nucleus, and electrons circling the nucleus.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>atom and the nitrosyl ligand – a molecule or ion that binds to a central metal atom or ion – in the Fe-NO complex, which limits how much information can be gained using traditional methods. The scientists employed advanced X-ray spectroscopic techniques at SSRL that allowed them to peer deeper into the chemical properties of the molecule and its bond, providing a more complete picture of the Fe-NO system and how it responds to light.

To follow up, the scientists plan to further explore the intricacies of the bond-breaking process and how to optimize the production of nitroxide or nitric oxide. They are also considering replacing iron with other metals to better understand the photoproduction process.

“In this research, we understand the starting molecule and its final products after shining light on it,” Gee said. “There are still a lot of nuances in the actual bond-breaking and release of nitroxide from this molecule that need to be explored. What step in the process decides the release of nitroxide instead of nitric oxide? How can we structurally tune the system to produce either molecule?”

Implications and Future Directions

This work helps build an understanding of which properties to monitor in future experiments at LCLS, where scientists will be able to take real-time snapshots of the nitroxide photogeneration process.

“The information we gained highlights the power of this approach and serves as a blueprint for future studies on these and similar molecules in the future that will extend to studies at the LCLS,” Gee said.

The research holds promise for the medical community and patients who might benefit from its future applications.

“Although we are still far away from using light on these molecules to treat serious cardiovascular conditions, fundamental insights in these molecules lay substantial groundwork for applied research in the future,” Gee said. “This may lead to entirely new ways to use light to treat cardiovascular conditions, microbial infections, cancer, and other health conditions.”

Reference: “Unraveling Metal–Ligand Bonding in an HNO-Evolving {FeNO}6 Complex with a Combined X-ray Spectroscopic Approach” by Leland B. Gee, Jinkyu Lim, Thomas Kroll, Dimosthenis Sokaras, Roberto Alonso-Mori and Chien-Ming Lee, 23 August 2023, Journal of the American Chemical Society.
DOI: 10.1021/jacs.3c04479

SSRL and LCLS are DOE Office of Science user facilities. This work was supported by the DOE Office of Science. SSRL’s Structural Molecular Biology Resource is funded by the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>National Institutes of Health and DOE Office of Science.

Source: SciTechDaily