Peptide drug improvement using vitamin B12 and haptocorrin binding substrate conjugates
Inventors
Assignees
Publication Number
US-11207415-B2
Publication Date
2021-12-28
Expiration Date
2037-04-14
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Abstract
The invention involves the coupling of compounds that can be bound by Haptocorrin (R-binder; Transcobalamin I; HC) to a target drug to improve pharmacokinetics, avoid undesirable side effects, and/or modify CNS access and localization. The pharmaceutical effect may be improved by conjugating the drug to haptocorrin binding substrate. This allows the conjugate to become bound to unsaturated haptocorrin in the blood, thereby protecting the drug from metabolism or excretion to increase protein half-life while not interfering with the efficacy of the protein drug. The conjugation may additionally prevent the drug from reaching the central nervous system or modify where the drug localizes and produces undesirable side effects such as nausea or hypophagia. Such a route also would prevent, in all case save for actual vitamin B12, binding by serum transcobalamin II (TCII), and thus not cause B12 deficiency with long term use.
Core Innovation
The invention provides an approach for improving the pharmaceutical effects of peptide drugs by conjugating them to compounds that can be bound by haptocorrin (R-binder; Transcobalamin I; HC), including vitamin B12, B12 derivatives, and cobinamides. This conjugation enables the peptide drug to bind to unsaturated haptocorrin in the blood, which protects the drug from metabolism or excretion and increases its half-life, without interfering with its efficacy.
The background identifies key challenges in peptide drug use, including their instability in serum due to protease degradation and the resulting short half-life, which hampers the development of peptide therapeutics. Existing methods, such as protein binding moieties and albumin conjugation, often inhibit drug efficacy and rely on post-administration release mechanisms. There is also a significant need to avoid undesirable side effects, particularly those involving the central nervous system such as nausea and hypophagia, which are noted with certain peptide therapeutics like GLP1-R agonists.
By coupling peptide drugs to haptocorrin binding substrates, the invention not only protects against degradation but can also prevent or modify the drug's access to the central nervous system. This can minimize or eliminate side effects such as nausea and hypophagia. Furthermore, by choosing substrates that bind selectively to haptocorrin but not transcobalamin II (except for natural B12s), the risk of inducing vitamin B12 deficiency with long-term use is avoided, addressing a major concern when using B12 conjugates for sustained treatments.
Claims Coverage
There are two independent claims, each introducing a main inventive feature involving conjugation of a peptide drug to a substrate that binds haptocorrin but not transcobalamin II in serum, where the substrate is dicyanocobinamide.
Method for improving pharmaceutical effect of peptide drug via haptocorrin-binding conjugation
A method comprising the step of conjugating a peptide drug to a substrate that binds to haptocorrin but not transcobalamin II in serum in the presence of B12 prior to administering the peptide drug intravenously or subcutaneously to a patient. The substrate used in this method is specifically dicyanocobinamide.
Compound of peptide drug conjugated to haptocorrin-binding substrate
A compound consisting of a peptide drug and a substrate that binds haptocorrin but not transcobalamin II in serum in the presence of B12, where the substrate is dicyanocobinamide and is conjugated to the peptide drug to provide improved pharmaceutical effect.
The inventive features claimed are focused on the conjugation of peptide drugs to dicyanocobinamide, a substrate with selectivity for haptocorrin over transcobalamin II, to improve pharmaceutical properties and reduce side effects.
Stated Advantages
Improves the pharmacokinetics of peptide drugs by increasing their half-life in the blood through protection from metabolism or excretion.
Avoids undesirable side effects, including central nervous system side effects such as nausea and weight loss (hypophagia), by modifying CNS access and localization.
Does not interfere with the efficacy of the protein or peptide drug, maintaining its desired therapeutic effects.
Prevents binding by serum transcobalamin II, thereby avoiding vitamin B12 deficiency with long-term use, except when using actual vitamin B12 compounds.
Documented Applications
Use with peptide drugs such as Exendin-4, amylin, PYY3-36, PYY1-36, GLP-1, Pramlintide, insulin, and others to improve pharmacokinetics and/or reduce undesirable side effects.
Mitigation of side effects, especially nausea and hypophagia, in therapies using GLP1-R agonists such as Exendin-4 for conditions like Type 2 diabetes mellitus.
Administration of peptide drug-haptocorrin substrate conjugates to animal models, such as rats or Chinese tree shrews, to compare effects on glucose control, nausea, and food intake.
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