Modified VIP Peptides for Extended Circulatory Half-Life
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The short half-life of vasoactive intestinal peptide (VIP) complicates its development as a pharmaceutical agent, and its multitude of biological effects make it impractical for specific therapeutic indications, necessitating modified versions with extended circulatory half-life and/or altered receptor-binding profiles.
Innovation Solution
Modified VIP molecules are recombinantly or chemically modified at the N- and/or C-termini with additional amino acids or fusion to heterologous sequences, such as Elastin-Like-Peptides (ELP), to enhance circulatory persistence and alter receptor binding profiles, reducing dosing frequency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If VIP is used as a pharmaceutical agent, then it provides beneficial biological effects on blood pressure and immune conditions, but its short half-life (less than 2 minutes) makes it impractical for therapeutic use
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of VIP, specifically replacing certain amino acids with D-amino acids (enantiomers) and incorporating non-natural amino acids. These chemical modifications change the molecular properties of VIP to resist proteolytic degradation, thereby extending its circulatory half-life from less than 2 minutes to potentially hours, making it therapeutically practical while maintaining its beneficial biological effects on blood pressure and immune conditions
Solution Approach 2:
The patent creates composite peptide structures by combining modified VIP sequences with heterologous amino acid sequences or peptide extensions. These composite structures include fusion proteins where VIP is linked to other peptide sequences that enhance stability and prolong circulation time, effectively creating a hybrid molecule that retains VIP's therapeutic effects while gaining extended duration of action
2Adaptability or versatility
If VIP is used to treat specific conditions, then it provides broad biological effects, but its multitude of effects on multiple receptors (VPAC1 and VPAC2) complicates development for particular indications
Solution Approach 1:
The patent applies local quality by making specific localized modifications to particular regions of the VIP molecule, especially at the N-terminus and C-terminus. By selectively modifying specific amino acid positions rather than the entire molecule, the invention alters receptor binding properties in a targeted manner, enabling preferential binding to either VPAC1 or VPAC2 receptors while maintaining other beneficial effects, thus simplifying the therapeutic profile for specific indications
Solution Approach 2:
The patent employs inversion by using D-amino acids (the enantiomers or mirror images of natural L-amino acids) in the VIP sequence. This chiral inversion fundamentally changes how the peptide interacts with receptors, allowing selective modulation of receptor binding affinity. By inverting the configuration of specific amino acids, the modified VIP can achieve preferential binding to one receptor type over another, reducing the complexity of managing multiple biological effects
Data Source
AI summary
The present invention provides modified Vasoactive Intestinal Peptides (VIPs), encoding polynucleotides and vectors, as well as pharmaceutical compositions comprising the same. The invention further provides methods of making and using the modified VIP agents. In accordance with the invention the VIP exhibits an extended circulatory half-life, receptor-binding or biological potency, and/or altered receptor binding profile with respect to unmodified VIP.