Peptide drug improvement using vitamin B12 and Haptocorrin binding substrate conjugates
Inventors
Assignees
Publication Number
US-12090208-B2
Publication Date
2024-09-17
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 centers on improving the pharmaceutical effects of peptide drugs by conjugating them to compounds that can bind haptocorrin, such as vitamin B12 derivatives or cobinamide. This conjugation allows the resulting drug complex to bind specifically to unsaturated haptocorrin in blood, thereby protecting the drug from metabolic degradation and excretion. This binding increases the half-life of the protein drug without affecting its efficacy at its target receptor.
Additionally, conjugation to haptocorrin-binding substrates like cobinamide can prevent the peptide drug from entering or improperly localizing within the central nervous system (CNS), thereby reducing or eliminating unwanted CNS side effects such as nausea or hypophagia. The invention also enables selective modification of CNS effects or localization, depending on the therapeutic need, without interfering with the essential role of vitamin B12 transport in the body.
The problem being addressed is the rapid degradation of peptide drugs in serum, which limits their therapeutic effectiveness due to instability and short half-life, as well as their propensity to produce undesirable CNS side effects. Prior art methods, such as albumin conjugation or general protein binding, can impair drug efficacy or require additional release mechanisms. The described invention overcomes these challenges by specifically leveraging haptocorrin binding to achieve both pharmacokinetic improvement and side-effect control without adversely impacting vitamin B12 metabolism.
Claims Coverage
The patent includes two independent claims, each focusing on core inventive features around the conjugation of peptide drugs with cobinamide enabling haptocorrin binding but avoiding transcobalamin II binding.
Conjugation of peptide drug to cobinamide for haptocorrin-specific binding
A method where a peptide drug is conjugated to an amount of cobinamide so that the resulting conjugate will bind to haptocorrin but not to transcobalamin II in serum, even in the presence of B12. This approach is directed toward improving the pharmaceutical effect of the peptide drug.
Compound of peptide drug bound to cobinamide with selective haptocorrin binding
A compound comprising a peptide drug and a cobinamide, with the cobinamide enabling binding to haptocorrin but not transcobalamin II in serum in the presence of B12. This results in an improved pharmaceutical effect.
In summary, the claims focus on the specific strategy of linking peptide drugs to cobinamide for selective haptocorrin binding, thus improving drug stability and specificity without engaging transcobalamin II.
Stated Advantages
Improved pharmacokinetics of peptide drugs by protecting against metabolism and increasing protein half-life.
Avoidance or reduction of undesirable central nervous system side effects such as nausea and weight loss.
Maintaining drug efficacy at its target receptor despite conjugation to haptocorrin binding substrates.
Prevention of B12 deficiency during long-term use, as the conjugates do not bind transcobalamin II except with actual B12 forms.
Documented Applications
Use in improving the pharmacokinetics and side-effect profile of peptide drugs such as Exendin-4, amylin, PYY3-36, PYY1-36, GLP-1, Pramlintide, and insulin.
Application to peptide drugs for reducing CNS side effects in therapeutic uses, including mitigation of nausea and appetite suppression.
Administration in preclinical animal models including rats and Chinese tree shrew for testing pharmacokinetics and side-effect profiles compared to unmodified peptide drugs.
Potential use in human therapies for conditions such as diabetes mellitus, with improved glucose regulation and lowered risk of weight loss and nausea.
Modification of drugs including anti-cancer substances, anti-AIDS substances, antibiotics, immunosuppressants, anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, anti-histamines, and other therapeutic agents as listed in the patent.
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