Analogues of parathyroid hormone (1-34) that function as agonists of the parathyroid hormone receptor-1 and display modified activity profiles

a technology of parathyroid hormone and receptor-1, which is applied in the field of analogues of parathyroid hormone, can solve the problems of low calcium in the blood, no rational method for designing such agonists, and people with hypoparathyroidism experience a number of unsettling symptoms

Inactive Publication Date: 2020-11-12
WISCONSIN ALUMNI RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Receptor state-selective agonists are highly prized because these molecules can serve as powerful tools for elucidating signal-transduction mechanisms, and they may give rise to therapeutic agents with minimal deleterious side effects.1,2 At present, there is no way to design such agonists via rational methods.
This then leads to low levels of calcium in the blood.
The main symptoms of hypoparathyroidism are the result of the low blood calcium level, which interferes with normal muscle contraction and nerve conduction.
As a result, people with hypoparathyroidism experience a number of unsettling symptoms, including paresthesia (an unpleasant tingling sensation around the mouth and in the hands and feet), muscle cramps, and tetany (severe spasms that affect the hands and feet).
However, such treatments are contra-indicated in many patients due to potential renal damage.

Method used

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  • Analogues of parathyroid hormone (1-34) that function as agonists of the parathyroid hormone receptor-1 and display modified activity profiles
  • Analogues of parathyroid hormone (1-34) that function as agonists of the parathyroid hormone receptor-1 and display modified activity profiles
  • Analogues of parathyroid hormone (1-34) that function as agonists of the parathyroid hormone receptor-1 and display modified activity profiles

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Abbreviations and Definitions

[0027]Agonist, Antagonist, Inverse Agonist: An inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist. A prerequisite for an inverse agonist response is that the receptor must have a constitutive level of activity in the absence of any ligand. An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level. An antagonist binds to the receptor and blocks the activity of both agonists and inverse agonists.

[0028]“Cyclically constrained” when referring to a β-amino acid or β-amino acid residue means a β-amino acid or β-amino acid residue in which the α-position and β-position carbon atoms in the backbone of the β-amino acid are incorporated into a substituted or unsubstituted C4 to C10 cycloalkyl, cycloalkenyl, or heterocycle moiety, wherein heterocycle moieties may have 1, 2, or 3 heteroatoms selec...

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Abstract

Described are polypeptide analogs of parathyroid hormone (PTH) that include an unnatural amino acid substitution at positions 7 or 8 from the N-terminus of the polypeptide. Also described are pharmaceutical compositions useful for treating hypoparathyroidism that contain the analogs and methods of using the analogs to treat hypoparathyroidism.

Description

FEDERAL FUNDING STATEMENT[0001]This invention was made with government support awarded under GM056414 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND[0002]Proper function of individual cells and entire organisms depends upon information transfer from the extracellular environment to the cytoplasm. Most signals must be transduced via proteins that span cellular membranes. Many receptor proteins do not act as simple, binary “toggle switches,” with only signaling-active and signaling-inactive states. Rather, they behave in vivo as nuanced interpreters of molecular information. This behavior enables the transmission of diverse messages based on variations in agonist structure. “Biased agonism” is one widely-studied manifestation of this complexity that has been documented for multiple G protein-coupled receptors (GPCRs).1,2 Signal transduction via these GPCRs involves multiple intracellular partners, only some of which are G pr...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/635
CPCA61K38/00C07K14/635
Inventor GELLMAN, SAMUEL H.LIU, SHI
Owner WISCONSIN ALUMNI RES FOUND
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