Compositions containing nucleosides and manganese and their uses
Inventors
Daly, Michael J. • Gaidamakova, Elena K. • Matrosova, Vera Y. • Levine, Rodney L. • Wehr, Nancy B.
Assignees
National Institutes of Health NIH • Henry M Jackson Foundation for Advancedment of Military Medicine Inc • US Department of Health and Human Services
Publication Number
US-9186406-B2
Publication Date
2015-11-17
Expiration Date
2028-08-18
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Abstract
This invention encompasses methods of preserving protein function by contacting a protein with a composition comprising one or more purine or pyrimidine nucleosides (such as e.g., adenosine or uridine) and an antioxidant (such as e.g., manganese). In addition, the invention encompasses methods of treating and/or preventing a side effect of radiation exposure and methods of preventing a side effect of radiotherapy comprising administration of a pharmaceutically effective amount of a composition comprising one or more purine or pyrimidine nucleosides (such as e.g., adenosine or uridine) and an antioxidant (such as e.g., manganese) to a subject in need thereof. The compositions may comprise D. radiodurans extracts.
Core Innovation
The invention provides methods and compositions for radioprotection by using one or more purine or pyrimidine nucleosides (such as adenosine or uridine) together with one or more antioxidants (such as manganese or manganous phosphate). These compositions preserve protein function and protect proteins from radiation-induced damage both in vitro and in vivo, including during exposure to various types of radiation like gamma rays, UV light, and X-rays. The compositions may be either synthetic or derived from protein-free cell extracts of the radiation-resistant bacterium Deinococcus radiodurans.
The problem addressed by the invention stems from the fact that most cells, including mammalian cells, are highly susceptible to radiation damage which induces protein oxidation and loss of function, leading to effects such as radiation sickness and increased cancer risk. Existing radioprotectors suitable for humans are limited and often cytotoxic with serious side effects. Deinococcus radiodurans has natural resistance attributed to manganese-based protein protection, but most organisms lack such mechanisms. Therefore, there is a significant need for non-toxic radioprotective compositions that preserve protein function and are suitable for human use.
The invention further encompasses methods of preparing ultrafiltered, protein-free D. radiodurans extracts that contain nucleosides and antioxidants which exhibit radioprotective properties. Additionally, the invention describes methods of treating or preventing side effects of radiation exposure or radiotherapy in subjects by administering these compositions. The compositions may also include amino acids such as leucine, valine, and alanine, which contribute to cytoprotective effects. Together, these innovations provide compositions and methods to protect proteins and cells from oxidative damage caused by radiation exposure.
Claims Coverage
The independent claims cover methods of protecting mammalian cells from ionizing radiation using protein-free ultrafiltrates derived from D. radiodurans with specific molecular weight and compositional characteristics.
Protein-free D. radiodurans ultrafiltrate for radioprotection
Administration of a protein-free D. radiodurans ultrafiltrate containing molecules of less than 3 kDa molecular weight to mammalian cells to protect them from ionizing radiation-induced damage.
Composition comprising specific nucleosides and antioxidants
The ultrafiltrate comprises one or more nucleosides selected from adenosine, uridine, β-pseudouridine, inosine, and mixtures thereof, as well as one or more antioxidants selected from manganese, MnCl2, and manganous phosphate.
Inclusion of amino acids to enhance protection
The ultrafiltrate includes amino acids selected from alanine, valine, and leucine to confer additional protective effects.
Defined concentration ranges of nucleosides and antioxidants
The concentrations of nucleosides are about 1 to about 15 mM of adenosine and/or uridine and antioxidants are about 1 to about 12.5 mM of manganese.
Method of producing the ultrafiltrate
Producing the protein-free D. radiodurans ultrafiltrate by harvesting, lysing, centrifuging to obtain supernatant, filtering with less than 3 kDa filter, and boiling for 15 to 45 minutes, yielding a boiling-resistant, cell-free extract.
Timing of administration for radioprotection
Administering the ultrafiltrate to mammalian cells prior to their exposure to ionizing radiation to prevent damage.
Protective effect against specified radiation-induced damages
Protection against radiation-induced damages including cell apoptosis, protein carbonylation, and protein oxidation within the cells.
In summary, the claims delineate a method using a specifically prepared, low molecular weight, protein-free D. radiodurans ultrafiltrate containing particular nucleosides, antioxidants, and amino acids at defined concentrations which when administered protects mammalian cells from ionizing radiation-induced molecular and cellular damage.
Stated Advantages
The compositions are relatively non-toxic compared to existing radioprotectors like amifostine.
The compositions strongly protect proteins from radiation-induced oxidation and preserve enzymatic function.
They provide potent radioprotection for mammalian and human T-cells exceeding other known radioprotective compounds.
The compositions protect against various side effects of radiotherapy, potentially improving safety during cancer treatments.
They are suitable for both pre-exposure prophylaxis and post-exposure therapeutic treatments including chronic radiation exposure scenarios.
Documented Applications
Methods of treating and preventing side effects of radiation exposure including radiation sickness and damage from UV, alpha, beta, gamma, X-ray, and neutron radiation.
Methods of preventing side effects of radiotherapy in humans undergoing cancer treatment involving various types of external and internal radiotherapy.
Preservation of protein function and enzymatic activity during exposure to radiation or desiccation to aid storage and longevity of biological products.
Radioprotection of cultured mammalian cells, including human T-cells, for research and therapeutic applications.
Provision of radioprotective compositions suitable for military personnel, nuclear industry workers, and astronauts exposed to ionizing radiation.
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