Conjugates of neurotensin or neurotensin analogs and uses thereof
The present invention features a compound having the formula A-X-B, where A is peptide vector capable of enhancing transport of the compound across the blood-brain barrier or into particular cell types, X is a linker, and B is a peptide therapeutic selected from the group consisting of neurotensin, a neurotensin analog, or a neurotensin receptor agonist. The compounds of the invention can be used to treat any disease in which increased neurotensin activity is useful and can be used to induce hypothermia or analgesia.
1. A compound having the structure:
2. A nucleic acid molecule encoding the compound of claim 1 .
3. A vector comprising the nucleic acid molecule of claim 2 , wherein said nucleic acid is operably linked to a promoter.
4. A method of making a compound, said method comprising expressing a polypeptide encoded by the vector of claim 3 in a cell, and purifying said polypeptide.
5. A method of making a compound of claim 1 , said method comprising synthesizing said compound on solid support.
6. A method of reducing body temperature of a subject, said method comprising administering a compound of claim 1 in an amount sufficient to reduce body temperature.
7. The method of claim 6 , wherein said subject is suffering from or has suffered from stroke, heart attack, cerebral ischemia, cardiac ischemia, or a nerve injury or is in need of neuroprotection.
8. The method of claim 7 , wherein said nerve injury is a brain or spinal cord injury.
9. The method of claim 8 , wherein said brain injury is a traumatic head or brain injury.
10. The method of claim 7 , wherein said subject is undergoing or is about to undergo a surgical procedure.
11. The method of claim 10 , wherein said surgical procedure is cardiac surgery or open heart surgery.
12. The method of claim 6 , wherein said subject is suffering from malignant hypothermia.
13. A method of treating pain or prophylactically treating pain in a subject, said method comprising administering a compound of claim 1 in an amount sufficient to treat said pain.
14. The method of claim 13 , wherein said pain is an acute pain selected from the group consisting of mechanical pain, heat pain, cold pain, ischemic pain, and chemical-induced pain.
15. The method of claim 13 , wherein said pain is peripheral or central neuropathic pain, inflammatory pain, migraine-related pain, headache-related pain, irritable bowel syndrome-related pain, fibromyalgia-related pain, arthritic pain, skeletal pain, joint pain, gastrointestinal pain, muscle pain, angina pain, facial pain, pelvic pain, claudication, postoperative pain, post traumatic pain, tension-type headache, obstetric pain, gynecological pain, or chemotherapy-induced pain.
16. A method of decreasing pain sensitivity in a subject, said method comprising administering an effective amount of a compound of claim 1 to said subject.
17. A method of treating a subject having a psychotic disorder, said method comprising administering a compound of claim 1 in an amount sufficient to treat said disorder, wherein said psychotic disorder is schizophrenia.
18. A method of treating a subject having a metabolic disorder, said method comprising administering a compound of claim 1 in an amount sufficient to treat said disorder.
19. The method of claim 18 , wherein said amount sufficient is less than 50% of the amount required for an equivalent dose of the neurotensin agonist when not conjugated to the peptide vector.
20. The method of claim 19 , wherein said amount is less than 15%.
21. The method of claim 18 , wherein said metabolic disorder is diabetes, obesity, diabetes as a consequence of obesity, hyperglycemia, dyslipidemia, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), diabetic dyslipidemia, hyperlipidemia, a cardiovascular disease, or hypertension.
22. A method of treating or treating prophylactically a neurological disorder in a subject, said method comprising administering a compound of claim 1 to said subject in an amount sufficient to treat or prevent said disorder, wherein said neurological disorder is schizophrenia, obsessive-compulsive disorder, or Tourette's syndrome.
23. The method of claim 22 , wherein the disorder neurological disorder is schizophrenia.
24. The method of claim 22 , wherein said neurological disorder is obsessive-compulsive disorder.
25. The method of claim 22 , wherein said neurological disorder is Tourette's syndrome.