Cyclic Peptides Targeting CD47 for Programmed Cell Death
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Solution Overview
Problem
Current therapeutic agents fail to effectively trigger programmed cell death (PCD) in cancers and immunological disorders associated with defects in PCD, particularly due to poor cell permeability and the activation of compensatory mechanisms, and existing peptides require high concentrations and have low potency.
Innovation Solution
Development of cyclic peptides mimicking the C-terminal binding domain of TSP-1 with high affinity and potency to trigger CD47-mediated PCD, offering nanomolar binding affinities and microM range efficacy, which are 100 to 1000 times more potent than previous linear peptides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If linear peptides are used to target CD47, then they can bind to CD47 and trigger PCD, but they require high concentrations and have low potency
Solution Approach 1:
The patent applies parameter changes by cyclizing the linear peptide structure to form cyclic peptides. This structural transformation changes the conformational flexibility and stability parameters of the peptide, resulting in nanomolar binding affinities and microM range efficacy - 100 to 1000 times more potent than previous linear peptides. The cyclic structure restricts conformational freedom, pre-organizing the peptide in its active conformation and enhancing CD47 binding affinity.
2Reliability
If current therapeutic agents are used, then they can be administered, but they fail to effectively trigger PCD due to poor cell permeability and activation of compensatory mechanisms
Solution Approach 1:
The cyclic peptides act as intermediaries that specifically bind to CD47 on the cell surface, triggering PCD through this target without requiring cell permeability. This extracellular mechanism of action avoids the harmful effect of activating intracellular compensatory mechanisms that plagues current therapeutic agents. The peptides mediate cell death signaling by engaging CD47's interaction with SIRPĪ± and other partners, bypassing the need for cellular internalization.
3Reliability
If high concentrations of peptides are used to achieve therapeutic effect, then PCD can be triggered, but the treatment requires larger doses and may increase off-target effects
Solution Approach 1:
The patent achieves dramatic improvement in potency parameters by transforming linear peptides into cyclic structures. This parameter change results in binding affinities in the nanomolar range and efficacy in the microM range, representing 100 to 1000 times increase in potency compared to linear peptides. Consequently, therapeutic doses can be reduced by two to three orders of magnitude while maintaining or enhancing PCD induction efficacy.
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 cyclic peptides induce apoptosis in cancer cells with high efficiency at lower concentrations, effectively targeting CD47 and addressing defects in PCD, demonstrating significant therapeutic potential for cancers and immunological disorders.
Implementation Method 1
Both pathways involve a cascade of protein-protein interactions (PPIs) and activations that results in a large variety of Programmed Cell Death types
Data Source
AI summary
The present invention relates to cyclic peptides mimetics of the C-terminal binding domain of TSP-1. The present invention also relates to the use of these cyclic peptides as agonists of CD47 and their ability to trigger programmed cell death (PCD). The present invention further relate to a pharmaceutical composition for use in the treatment of diseases associated with defects in PCD such as cancers and immunological disorders (including chronic inflammation) and comprising at least one cyclic peptide according to the invention.