Selective Polypeptide Binding Heparan Sulfate for Targeted Delivery
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Solution Overview
Problem
Current cell-penetrating peptide (CPP)-based delivery systems lack selectivity between healthy cells and cancer cells, leading to side effects and limiting their biomedical application, as they do not specifically target cells expressing heparin or heparan sulfate glycosaminoglycans.
Innovation Solution
A novel polypeptide sequence, RK-XXX-KK-XXXXXX-KR, where X represents specific amino acids, is discovered to selectively bind to cells expressing heparin or heparan sulfate, enabling targeted delivery of therapeutic molecules by linking with a cell internalization peptide for internalization into cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cell-penetrating peptides are used for delivery, then therapeutic molecules can be delivered into cells, but the system lacks selectivity between healthy cells and cancer cells causing side effects
Solution Approach 1:
The patent applies local quality by creating a polypeptide with a specific amino acid sequence (RK-XXX-KK-XXXXXX-KR) that is selectively attracted to heparin/heparan sulfate-rich environments. This localized chemical property enables the peptide to preferentially target cancer cells over healthy cells, resolving the contradiction between delivery capability and selectivity.
Solution Approach 2:
The patent changes the chemical parameters of the delivery system by incorporating a specific polypeptide sequence with known binding affinity for heparin/heparan sulfate. This parameter change enables selective interaction with cancer cells that overexpress these glycosaminoglycans, thereby improving reliability while reducing harmful effects on healthy cells.
2Reliability
If cell-penetrating peptides are used to cross cell membranes, then internalization is achieved, but specificity for cancer cells expressing heparin or heparan sulfate is not obtained
Solution Approach 1:
The polypeptide sequence RK-XXX-KK-XXXXXX-KR was designed with specific local chemical properties that create high affinity binding to heparin/heparan sulfate. This localized quality enables selective targeting of cancer cells that overexpress these glycosaminoglycans, achieving both internalization capability and cancer cell specificity simultaneously.
Solution Approach 2:
The patent uses heparin/heparan sulfate as an intermediary target on the cell surface. The polypeptide binds to these glycosaminoglycans as a mediator step before internalization occurs. This intermediary mechanism provides specificity for cancer cells while maintaining the ability to penetrate cell membranes through the same binding interaction.
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
The polypeptide effectively targets and internalizes into cells expressing heparin or heparan sulfate, enhancing the specificity and efficacy of therapeutic delivery while minimizing side effects on healthy cells.
Implementation Method 1
GAGs are composed of different repeating disaccharide units... negatively charged due to their sulfated groups and carboxyl groups... The third helix is responsible for the internalization activity of the protein... Penetratin is a cell-penetrating peptide (CPP)... CPPs interact with the different biomolecules at the cell surface
Implementation Method 2
CPPs are a large family of peptides generally containing 5-30 amino acids and own the characteristic of spontaneously crossing the cell membrane... Their positive charges intrinsically represent the major common properties of CPPs... The first CPPs Penetratin (Pen) and Tat are respectively from Antennapedia (Antp) transcription factor and the trans-activator protein of transcription of human immunodeficiency virus-1 (HIV-1)
Implementation Method 3
Homeoproteins (HPs) are autonomous transcription factors that are active during development and in adulthood... These proteins are found ubiquitously in plant and animal cells... HPs have paracrine activities and can travel from cell to cell through unconventional transfer or transduction pathway... Their intracellular activity implies a direct access of the traveling proteins to the cytosol and nucleus of recipient cells
Data Source
AI summary
The present invention relates to a polypeptide X1X2-RK-X3X4-KK-X5X6X7X8X9X10-KR-X11X12 SEQ ID NO: 1 able to bind selectively to cells expressing proteoglycans comprising glycosaminoglycans as heparin or heparan sulfate. The linkage of said polypeptide to an internalization peptide enables the polypeptide to be internalized.The present invention further relates to a conjugated polypeptide comprising said polypeptide and a biomarker, to a cell penetrating polypeptide comprising said polypeptide, optionally a linker and a cell internalization peptide and a chimeric polypeptide comprising said cell penetrating polypeptide and one or more biological cargos.