MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation

Abstract

The radioprotective capacity of a rationally-designed Mn2+-decapeptide complex (MDP), based on Mn antioxidants in the bacterium Deinococcus radiodurans, was investigated in a mouse model of radiation injury. MDP was previously reported to be extraordinarily radioprotective of proteins in the setting of vaccine development. The peptide-component (DEHGTAVMLK) of MDP applied here was selected from a group of synthetic peptides screened in vitro for their ability to protect cultured human cells and purified enzymes from extreme damage caused by ionizing radiation (IR). We show that the peptides accumulated in Jurkat T-cells and protected them from 100 Gy. MDP preserved the activity of T4 DNA ligase exposed to 60,000 Gy. In vivo, MDP was nontoxic and protected B6D2F1/J (female) mice from acute radiation syndrome. All irradiated mice treated with MDP survived exposure to 9.5 Gy (LD70/30) in comparison to the untreated mice, which displayed 63% lethality after 30 days. Our results show that MDP provides early protection of white blood cells, and attenuates IR-induced damage to bone marrow and hematopoietic stem cells via G-CSF and GM-CSF modulation. Moreover, MDP mediated the immunomodulation of several cytokine concentrations in serum including G-CSF, GM-CSF, IL-3 and IL-10 during early recovery. Our results present the necessary prelude for future efforts towards clinical application of MDP as a promising IR countermeasure. Further investigation of MDP as a pre-exposure prophylactic and post-exposure therapeutic in radiotherapy and radiation emergencies is warranted.

Across the tree of life, radiation resistance is governed by antioxidant Mn 2+ , gauged by paramagnetic resonance

“…S4 ( 32 ); for completeness, collection and analysis of the full Mn 2+ Sod spectrum here ( SI Appendix , Fig. S6 ) now confirm the reported magnitudes of the parameters that define the EPR spectrum of MnSod [the so-called zero-field splitting (ZFS) parameters], and further yield the sign of the dominant parameter ( 23 , 24 ) ( SI Appendix , Materials and Methods ).…”

“…In this regard, Mn 2+ in D. radiodurans cells, which are extremely IR-resistant, exists almost exclusively as antioxidant H-complexes, whereas Mn 2+ in E. coli cells, which are IR-sensitive, exists primarily as L-complexes ( 15 ). In vivo, H-Mn 2+ complexes in bacteria protect proteins, but not DNA, from IR-induced ROS ( 7 , 11 , 18 , 19 ); similarly, synthetic H-Mn 2+ complexes provide strong in vitro protection of proteins, but not DNA, from ROS ( 11 , 19 – 24 ). Moreover, H-Mn 2+ –accumulating yeasts consistently display elevated ROS-scavenging capacities ( Fig.…”

“…Such intracellular Mn antioxidants globally protect the proteome, and, logically, this must include DNA repair enzymes, from extreme oxidative assault during irradiation ( 5 ). Rationally designed Deinococcus Mn antioxidants display similar properties in vitro ( 19 – 21 ); they protect proteins from IR but not DNA or RNA, and are now used in the production of irradiated vaccines ( 22 , 23 ) and as in vivo radioprotectors ( 24 ). Consistent with this focus on Mn 2+ antioxidant complexes, we showed by absorption-display electron paramagnetic resonance (EPR) spectroscopy that the Mn 2+ of D. radiodurans exists predominantly as high-symmetry (H) LMW complexes with phosphate, nitrogenous, and other metabolites, with no evidence for significant amounts of Mn 2+ bound to MnSod ( 15 ).…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use

“…Earlier, MDP was demonstrated to protect proteins from radiation-induced damage following ultra-high exposures, but failed to protect DNA or RNA under similar exposure conditions (Gaidamakova et al 2012). This agent was found to be non-toxic and significantly protected B6D2F1/J mice exposed to 9.5 Gy TBI (LD 70/30 ) when administered sc (300 mg/kg, once daily starting from day -1 to day 7, also po 14 h prior to TBI and immediately post-irradiation) (Gupta et al 2016). MDP provided protection against excessive loss of WBC, and it attenuated radiation-induced damage to BM and hematopoietic cells via modulation of G-CSF and granulocyte-macrophage-colony stimulating factor (GM-CSF).…”

Distributions of manganese in diverse human cancers provide insights into tumour radioresistance

“…Not only is the survival of irradiated cells in culture massively increased, but so also is the survival of mice given whole body radiation. 18 The existence of radioprotective Mn…”