Conjugates of neurotensin or neurotensin analogs and uses thereof

Abstract

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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application Nos. 61 / 225,486, filed Jul. 14, 2009; 61 / 181,144, filed May 26, 2009; and 61 / 200,947, filed Dec. 5, 2008, each of which is hereby incorporated by reference.BACKGROUND OF THE INVENTION[0002]The invention relates to compounds including neurotensin, a neurotensin analog, or a neurotensin receptor agonist bound to a peptide vector and uses thereof. Neurotensin is 13 amino acid peptide possessing numerous biological activities. Injections of neurotensin in the central nervous system produce, among other effects, antipsychotic and hypothermic effects. Intravenous delivery of neurotensin, however, does not result in these effects, as the blood-brain barrier (BBB) effectively prevents peripheral neurotensin from reaching the receptors in the central nervous system (CNS) receptors.[0003]Reduction of body temperature (hypothermia) provides one of the best forms of neuroprotection a...

AI Technical Summary

Benefits of technology

[0008]Neurotensin, by itself, is unable to cross the BBB. We have therefore synthesized compounds that include (a) a polypeptide therapeutic selected from the group consisting of neurotensin, a neurotensin analog (e.g., pELYENKPRRPYIL-OH, where “pE” represents L-pyroglutamic acid, human neurotensin(8-13) (NT(8-13)), Ac-Lys-[D-Tyr11]NT(8-13), Ac-Lys-NT(8-13), pE-Lys-NT(8-13),), or a neurotensin receptor agonist and (b) a peptide vector capable of transporting the peptide therapeutic across the blood-brain barrier (BBB) or into particular cell types. These compounds are useful in treating any disorder where increased neurotensin activity is desired, particularly where transport of the polypeptide therapeutic across the BBB or into a particular cell type is desired. In one particular example, the compound includes neurotensin or a neurotensin fragment which may be used to reduce body temperature (e.g., in a patient who is in need of neuroprotection and / or has had a stroke, heart attack, nerve injury (e.g., spinal chord, head, or brain injury, such as a traumatic brain injury, or is having major surgery such as cardiac surgery or open heart surgery), to treat a patient suffering from a psychiatric disorder (e.g., schizophrenia, obsessive compulsive disorder, or Tourette's syndrome), or to treat a patient suffering from a metabolic disorder such as diabetes and obesity. In other cases, the compound may be able to either increase or reduce blood pressure in a patient.

[0009]The compound may be capable of inducing hypothermia, upon either a single or upon an infusion for a period of at least 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, 24, 30, 36, or 48 hours following initial administration. The peptide vector is capable of transporting the polypeptide therapeutic either across the blood-brain barrier (BBB) or into a particular cell type (e.g., liver, lung, kidney, spleen, and muscle). Because the conjugates are targeted across the BBB or to particular cell types, therapeutic efficacy can be achieved using lower doses or less frequent dosing as compared to the unconjugated peptide therapeutic, thus reducing the severity of or incidence of side effects and / or increasing efficacy. The compound may also exhibit increased stability, improved pharmacokinetics, or reduced degradation in vivo, as compared to the unconjugated peptide therapeutic.

[0023]In any of the methods involving administration of a compound to a subject, the amount sufficient may be less than 90%, 75%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.1% of the amount required for an equivalent dose of the polypeptide therapeutic (e.g., any described herein) when not conjugated to the peptide vector. The amount sufficient may reduce a side effect as compared to administration of an effective amount of the polypeptide therapeutic when not conjugated to the peptide vector. The subject may be a mammal such as a human.

[0034]By “treating prophylactically” a disease, disorder, or condition in a subject is meant reducing the frequency of occurrence or severity of (e.g., preventing) a disease, disorder or condition by administering to the subject a therapeutic agent to the subject prior to the appearance of a disease symptom or symptoms.

Problems solved by technology

These techniques can be complex and expensive, and can lead to delays in the onset of hypothermia.

Sustained maintenance of hypothermia may also be difficult using these methods.

Finally, these methods can cause severe shivering, necessitating the need for co-medications such as paralytic agents or sedatives.

In the development of a new therapy for brain pathologies, the BBB is considered a major obstacle for the potential use of drugs for treating disorders of the CNS.

This may explain the lack of therapeutic options available for major neurological diseases.

The brain endothelium, which constitutes the BBB, represents the major obstacle for the use of potential drugs against many disorders of the CNS.

Many drugs that have a larger size or higher hydrophobicity show high efficacy in CNS targets but are not efficacious in animals as these drugs cannot effectively cross the BBB.

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