Modified Glycoprotein Hormone Half-Life Extension via Alpha Subunit Segmentation
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Solution Overview
Problem
Previous modified glycoprotein hormones exhibited increased receptor affinity but were cleared quickly, lacking improved biological half-life and bioavailability, which is essential for a clinically useful superagonist.
Innovation Solution
A modified glycoprotein hormone with an alpha subunit polypeptide of bovine follicle-stimulating hormone (FSH) featuring amino acid inserts and substitutions, such as at positions 6 or 7 and basic amino acid substitutions at specific positions, to enhance pharmacological properties like receptor binding affinity and biological half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If modified glycoprotein hormones are designed to increase receptor affinity, then binding affinity is improved, but biological half-life is reduced
Solution Approach 1:
The hormone is divided into two subunits (alpha and beta) that can be independently modified. The alpha subunit contains the amino acid substitutions and peptide inserts to extend half-life, while the beta subunit maintains receptor specificity. This segmentation allows optimization of different properties in different parts of the molecule.
Solution Approach 2:
Specific local modifications are made to the alpha subunit at particular positions (substitutions at positions 15, 17, 18, 20, 24 and inserts at positions 6 or 7) without altering the entire molecule. These localized changes provide extended half-life while preserving the overall hormone structure and receptor binding capability.
2Power
If modified glycoprotein hormones are designed to increase potency, then receptor affinity is improved, but clearance rate increases
Solution Approach 1:
The physical-chemical parameters of the hormone are changed by introducing basic amino acid substitutions and peptide inserts with potential glycosylation sites. These parameter changes increase molecular weight and alter charge distribution, which slows clearance while maintaining or enhancing potency through improved receptor interaction.
Solution Approach 2:
The hormone is constructed as a composite of the native glycoprotein structure with added peptide sequences. This composite structure combines the high-potency core hormone with extended peptide regions that resist degradation and slow clearance, creating a molecule with both high potency and prolonged persistence.
Data Source
Figure 1A~1B
Figure 1C
Figure 2A~2B
AI summary
This invention provides long-acting, superactive analogs of glycoprotein hormones demonstrating enhanced bioactivity both in vitro and in vivo as compared to wild type counterparts. The analogs are particularly useful for treating subjects showing low receptor expression or poor receptor responsiveness, and for the treatment of any condition associated with glycoprotein hormone activity.