Peptide Derivatives for Blood-Brain Barrier Transport via LDLR Binding
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Solution Overview
Problem
Current methods for delivering therapeutic and diagnostic molecules across the blood-brain barrier (BBB) are inefficient due to the barrier's impermeability, limiting the treatment of central nervous system (CNS) disorders such as brain cancer, Parkinson's, and Alzheimer's, as most molecules cannot cross the BBB and are either too large or actively expelled by efflux systems.
Innovation Solution
Development of peptide derivatives that bind to the low-density lipoprotein receptor (LDLR) on the BBB, allowing for the transport of therapeutic and diagnostic molecules across the BBB without competing with natural ligands, and can be designed to be small enough to cross cell membranes effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If molecules are made larger to improve therapeutic efficacy, then treatment effectiveness is improved, but the ability to cross the BBB deteriorates
Solution Approach 1:
The patent employs receptor-mediated transcytosis where large therapeutic molecules are nested within carrier vehicles (such as liposomes or protein carriers) that are themselves transported across the BBB via receptor binding. This allows large molecules to be delivered intact to the brain by hiding them within smaller transportable carriers that can exploit endogenous transport pathways.
Solution Approach 2:
The patent uses specific receptors (such as transferrin receptor, LDL receptor, or insulin receptor) as intermediaries to facilitate the transport of large therapeutic molecules across the BBB. These receptors naturally mediate substance transport across the blood-brain barrier and are exploited to carry therapeutic agents that would otherwise be excluded.
2Reliability
If peptide length is increased to improve binding affinity, then receptor binding is improved, but membrane permeability deteriorates
Solution Approach 1:
The patent optimizes peptide parameters by identifying and utilizing specific short amino acid sequences (typically 5-20 residues) that achieve sufficient binding affinity while maintaining the size and physicochemical properties necessary for membrane permeability. This involves changing parameters such as amino acid composition, charge distribution, and hydrophobicity to balance binding and permeation.
Solution Approach 2:
The patent applies local quality by concentrating binding activity in specific localized regions of the peptide structure rather than requiring uniform interaction along the entire peptide chain. This allows short peptides to achieve high affinity through focused interactions at critical binding sites while maintaining overall small size for permeability.
3Length of moving object
If peptide size is reduced to improve BBB crossing, then membrane permeability is improved, but binding affinity deteriorates
Solution Approach 1:
The patent changes peptide parameters by selecting specific amino acid sequences and modifications that maximize binding efficiency per unit length. This includes optimizing charge, hydrophobicity, and specific residue composition to achieve high affinity with minimal peptide length, enabling both small size and strong binding.
Solution Approach 2:
The patent creates composite structures by combining short peptide sequences with other molecular components (such as lipids, sugars, or aromatic groups) that contribute to binding affinity. This composite approach allows the peptide portion to remain small for permeability while the combined structure achieves high binding affinity through multiple interaction mechanisms.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These peptide derivatives improve the bioavailability and access of molecules to the CNS, enabling effective treatment and diagnosis of neurological and infectious pathologies by facilitating the transport of molecules that normally cannot cross the BBB.
Implementation Method 1
peptide derivatives that bind to the low-density lipoprotein receptor (LDLR) on the BBB, allowing for the transport of therapeutic and diagnostic molecules across the BBB
Data Source
AI summary
The invention relates to peptide derivatives (peptides and pseudo-peptides) and use thereof as vectors for molecules of interest. The invention also relates to conjugates containing a peptide derivative of the invention bound to a molecule of interest. The peptides and prodrug conjugates of the invention can be used to vectorize molecules of pharmaceutical or diagnostic interest, such as, for example, therapeutic molecules, imaging or diagnostic agents, or molecular probes, across cell membranes, and notably to promote their transport across the blood-brain barrier (BBB).