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Synthetic Oxynor Analog of Beta Taipoxin, for Cell Growth and Wound Healin

(1) US Patent 6,316,602 B1, 2001,
Beta Taipoxin as a Cell Growth Factor and Method.

(2) US patent 7,129,334 B2, 2006
Synthetic Peptide Oxynor and the Uses for the same.

The venom of Australian taipan snake (Oxyuranus s. scutellatus) is extremely potent due to the presence of taipoxin. The intact complex molecule of taipoxin having molecular weight 45.6 kDa is composed of three subunits a, b and gama. The identified mitogenic fragment consisted of 21 amino acids. HPLC fractionation of crude venom permits the separation of subunits. The mitogenic activity was revealed in non toxic b Taipoxin, showing the activity on variety of eukaryotic cells. Its activity as a mitogen extends to wound healing in experimental animals.

Identification of Active Mitogenic Domain of b taipoxin and its conversion to Synthetic Oxynor. By lengthy complicated research, the active domain of beta taipoxin having mitogenic property was identified and isolated. After drug discovery, a synthetic peptide consisting of ten amino acids was constructed named Oxynor, having sequence S L L N F A N L I E. Oxynor mimics the biological properties of natural b taipoxin consisting of 120 amino acids in vitro and in vivo systems.

Table 1. Comparison of growth stimulating effect of b-taipoxin and
Oxynor on PC12 cells in serum free medium.

*Initial cell count of PC12 cells was 105 cells/ml

Results of table 1 show that the addition of 0.1µg/ml of b-taipoxin gave growth of PC12 cells comparable to the medium containing 10% serum, which proves its remarkable mitogenic property. The concentration of Oxynor required to be effective was ten times, 500 µg incomparison to b-taipoxin. Incorporation of Oxynor in the medium produced neurite outgrowth on PC12 cells. This illustrates the neurotrophic property for b-taipoxin and Oxynor similar to nerve growth factor (NGF).

In Vivo Wound Healing: Experimentally produced 4 mm punched wounds on the back of the mice were treated with b-taipoxin or Oxynor. The wounds of the mice were treated daily for seven consecutive days at the concentrations of 100 µg/wound for b-taipoxin versus 500 µg/wound for Oxynor, in 100 µl volume.

Table 2: Wound healing by treatment with Oxynor and b-taipoxin

The results showed complete closure of the wounds after six days while the wounds of controls treated with PBS were open. Microscopic histology examination of the skin around the wounds revealed that the treated mice showed re-epithelialization of the epidermis, which looked close to the normal mouse skin biopsy; whereas, the controls showed distortion of epithelium.

Natural b-taipoxin and Oxynor were tested for comparison in vivo at the concentration of 100 µg/ml in hydrogel vehicle applied once daily to help heal 6 mm ischemic skin wounds in rats. At days 7 and 14 wounds treated with b-taipoxin were 15 % smaller in area than the wounds treated with Oxynor. This demonstrates that Oxynor is as efficacious as natural b-taipoxin under the conditions of the test. On increasing the concentration of Oxynor to 500 µg/ml should give equivalent wound closure to 100 µg/ml b-taipoxin. Thus Oxynor is proved to be a potent wound healing drug having neurotrophic and keratinous property. These experiments were performed at the University of Florida by by Dr. Schultz figures 1 & 2.

Figure 1. Area of wounds on day 7 treated with b- taipoxin and Oxynor.

Figure 2.

Keratinocytic property of Oxynor: In humans, application of Oxynor on bald scull helps grow hair and also returns gray hair to its original younger looking color, again showing keratinocyte activity. On applying b-taipoxin daily for four to six weeks on (1) a chronic wound and (2) diabetic ulcer caused healing completely without scaring. Thus, it proves that Oxynor is a potent mitogen having neurotrophic and keratinocyte properties with great potential for wound healing.