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

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...

AI Technical Summary

Benefits of technology

This patent describes a method for creating peptide analogs of PTH that display biased agonist activity relative to β arrestin recruitment. These analogs can be designed by replacing certain amino acids in the natural peptide with unnatural amino acids or D-stereoisomers. The resulting peptides can exhibit altered receptor preferences and have potential to display different behaviors in vivo. The patent also describes the use of backbone modification to achieve biased agonism. The resulting peptides can be used as therapeutic agents for the treatment of disorders associated with PTH receptors.

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.

Images