Methods of altering the binding affinity of a peptide to its receptor

Abstract

The present invention relates to amphiphilic drug-oligomer conjugates capable of traversing the blood-brain barrier ("BBB") and to methods of making and using such conjugates. An amphiphilic drug-oligomer conjugate comprises a therapeutic compound conjugated to an oligomer, wherein the oligomer comprises a lipophilic moiety coupled to a hydrophilic moiety. The conjugates of the invention further comprise therapeutic agents such as proteins, peptides, nucleosides, nucleotides, antiviral agents, antineoplastic agents, antibiotics, etc., and prodrugs, precursors, derivatives and intermediates thereof, chemically coupled to amphiphilic oligomers.

Description

[0001] This application is a divisional application of U.S. patent application Ser. No. 09 / 134,803, filed Aug. 14, 1998, allowed, the disclosure of which is incorporated herein by reference in its entirety.1. BACKGROUND OF THE INVENTION[0002] 1. Field of the Invention[0003] The present invention relates to amphiphilic oligomer conjugates capable of traversing the blood-brain barrier ("BBB") and to methods of making and using such conjugates. The conjugates of the invention comprise therapeutic agents such as proteins, peptides, nucleosides, nucleotides, antiviral agents, antineoplastic agents, antibiotics, etc., and prodrugs, precursors, derivatives and intermediates thereof, chemically coupled to amphiphilic oligomers.[0004] 2. Description of the Related Art[0005] In the field of pharmaceutical and therapeutic invention and the treatment of disease states and enhancement of physiological conditions associated with the CNS, a wide variety of therapeutic agents have been developed, i...

AI Technical Summary

Benefits of technology

[0068] In another aspect, PEG is used as a spacer group in the amphiphilic conjugate and the length and number of the PEG moieties can be varied to refine the amphiphilicity of the conjugate. Increasing the number of PEGs increases the hydrophilicity of the conjugate.

[0072] In another aspect, a pharmaceutical composition is provided comprising (1) a mixture of an enkephalin conjugate according to the present invention wherein the enkephalin peptide has proline or alanine added to its N-terminus and an enkephalin conjugate according to the present invention which does not have a proline or alanine added to the N-terminus, and (2) a pharmaceutical carrier. This aspect provides a faster acting sustained dose of enkephalin.

Problems solved by technology

However, a number of obstacles currently limit the use of many compounds for use as CNS therapeutic agents.

The BBB has about 1000 times more surface area than the choroid plexus and is the primary obstacle to delivery of therapeutic compounds to the CNS.

A further barrier to peptide delivery to the CNS is metabolic instability.

Metabolically stablized peptides may exhibit increased resistance to certain enzymes; however, it has not been possible to protect peptides from the wide range of peptide-degrading enzymes present in the blood and BBB.

Another difficulty inherent in delivering peptides to the BBB is that successful transcytosis is a complex process which requires binding at the lumenal or blood side of the brain capillary endothelium, movement through the endothelial cytoplasm, and exocytosis at the ablumenal or brain side of the BBB.

In any event, many currently existing drug substances, especially peptides, are unable to overcome these structural and metabolic barriers to enter the BBB in sufficient quantities to be efficacious.

Aside from general considerations relating to the invasiveness of mechanical procedures, a major difficulty with mechanical approaches is the lack of peptide distribution.

This lack of distribution is due in part to rapid exportation of peptides to the peripheral circulation.

Such procedures have considerable toxic effects, including inflammation, encephalitis, etc.

Furthermore, such procedures are not selective: the opening of the tight junctions of the BBB permits many undesirable substances to cross the BBB along with the therapeutically beneficial molecule.

While the risks involved in these invasive procedures may be justified for life-threatening conditions, they are generally not acceptable for less dramatic illnesses.

A difficulty with the prodrug approach to crossing the BBB is that the cleavage necessary to yield an active drug may not occur with sufficient efficiency and accuracy to produce an efficacious amount of the drug.

A further difficulty with lipidized prodrugs is that they pass in and out of the CNS so readily that they may never reach sufficient concentration in the CNS to achieve their intended function.

However, these strategies required the subcutaneous delivery of frequent and massive doses of peptide to induce analgesia.

Frequent and / or massive dosing is inconvenient to the patient and may result in serious side effects.

However, the difficulty with this system is designing a chimeric molecule which can become detached upon entry into the interstitial space; to the inventor's knowledge, this has not yet been achieved.

Additionally, the poor stoichiometry of the neuropeptide to the carrier molecule limits the mass of the target peptide.

Furthermore, receptor-mediated cellular transport systems typically have physiologically limited transport capacity.

This is a rate-limiting factor which can prevent entry of pharmaceutically active amounts of peptide.

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