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
Henry M Jackson Foundation for Advancedment of Military Medicine Inc • US Department of Health and Human Services
Publication Number
US-10342871-B2
Publication Date
2019-07-09
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
This invention provides methods of preserving protein function by contacting a protein with a composition comprising one or more purine or pyrimidine nucleosides (such as adenosine or uridine) and one or more antioxidants (such as manganese). It also encompasses methods of treating and/or preventing side effects of radiation exposure, including radiotherapy, by administering pharmaceutical compositions containing these components to subjects in need. The compositions may be derived from D. radiodurans extracts and are effective against various types of radiation including UV light, alpha, beta, gamma, X-ray, and neutron radiation.
The problem addressed by this invention arises from the sensitivity of most proteins and cells, including mammalian cells, to radiation damage, notably protein oxidation induced by ionizing radiation. Unlike the radiation-resistant bacterium Deinococcus radiodurans, which survives high doses of radiation due to protein protection mediated by manganese accumulation and nucleosides, human and other cells suffer significant damage leading to side effects including radiation sickness and cancer. Existing radioprotectors suitable for humans, such as amifostine, have cytotoxicity and undesirable side effects, thus creating a need for non-toxic radioprotectors that preserve protein function and are suitable for human use.
The invention was developed based on the discovery that D. radiodurans protein-free cellular ultrafiltrates, containing purine or pyrimidine nucleosides and manganese-based antioxidants, exhibit potent radioprotective effects by preventing ionizing radiation-induced oxidation of proteins and preserving their function. Synthetic compositions mimicking these components also confer radioprotection in vitro and in vivo, including protection of mammalian cells from radiation-induced apoptosis. The compositions may additionally include amino acids such as leucine, valine, and alanine, further enhancing cytoprotective effects. Methods for preparing the D. radiodurans extracts involve harvesting, lysing, filtering, and boiling steps, yielding a soluble, cell-free, and heat-resistant product containing the protective components.
Claims Coverage
The patent contains two independent claims covering methods of protecting and treating side effects of radiation exposure using compositions derived from protein-free D. radiodurans ultrafiltrates.
Method of protecting against radiation side effects using protein-free D. radiodurans ultrafiltrate
Administration of a pharmaceutical composition comprising a protective amount of a protein-free D. radiodurans ultrafiltrate to human subjects, where the ultrafiltrate excludes molecules over 3 kiloDaltons, for protection against side effects of radiation exposure.
Method of treating side effects of radiation therapy with protein-free D. radiodurans ultrafiltrate
Administration of a pharmaceutical composition comprising a protective amount of a protein-free D. radiodurans ultrafiltrate to human subjects suffering side effects of radiation therapy, where the ultrafiltrate excludes molecules over 3 kiloDaltons.
The independent claims focus on methods of protection and treatment of radiation side effects in humans by administering compositions of protein-free D. radiodurans ultrafiltrate containing purine nucleosides and antioxidants, with molecular weight filtering below 3 kD, thereby defining compositions and methods utilizing these specific components for radioprotection.
Stated Advantages
Compositions comprising purine and pyrimidine nucleosides along with antioxidants are relatively non-toxic compared to established radioprotectors such as amifostine.
These compositions preserve protein function and protect against a broad spectrum of radiation types, including ionizing radiation and UV radiation.
The methods provide effective pre- and post-exposure treatments suitable for military personnel, civilians accidentally exposed to radiation, and individuals exposed to chronic radiation such as nuclear workers or astronauts.
Documented Applications
Preserving protein function during exposure to various forms of radiation including UV light, alpha, beta, gamma, X-ray, and neutron radiation.
Preventing or treating side effects of radiation exposure and radiotherapy in human subjects.
Use of D. radiodurans extracts or synthetic compositions containing purine or pyrimidine nucleosides and manganese-based antioxidants as radioprotective agents.
Topical administration of protective compositions to prevent radiation-induced tissue damage.
Potential prophylactic use for individuals exposed to chronic levels of radiation, including in nuclear power plants and during long-duration space missions.
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