VDAC1-Derived Peptides for Cancer Apoptosis via CPP Conjugation
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Solution Overview
Problem
Current therapeutic agents for inducing cancer cell apoptosis are limited by resistance mechanisms in cancer cells, particularly due to overexpression of anti-apoptotic proteins like HK-I, which hinders the effectiveness of chemotherapy and existing peptide-based therapies face challenges with stability, permeability, and specificity.
Innovation Solution
Development of short synthetic peptides based on the VDAC1 N-terminal domain, conjugated with cell-penetrating peptides, that are more stable and active, specifically inducing apoptosis in cancer cells by impairing energy production and enhancing sensitivity to apoptosis-inducing agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional peptide-based therapies are used to induce cancer cell apoptosis, then they can target VDAC1 and initiate cell death pathways, but they face challenges with stability, permeability, and resistance mechanisms in cancer cells
Solution Approach 1:
The patent modifies peptide parameters by using D-amino acids instead of L-amino acids, changing the stereochemical configuration to resist proteolytic degradation. This parameter change improves peptide stability while maintaining the ability to induce apoptosis in cancer cells by targeting VDAC1.
Solution Approach 2:
The patent creates composite structures by conjugating the VDAC1-targeting peptide with cell-penetrating peptides (CPPs). This composite approach combines the apoptosis-inducing capability of the VDAC1-targeting peptide with the membrane permeability enhancement of CPPs, overcoming both stability and permeability challenges.
2Ease of operation
If existing peptide therapies are used, then they can interact with VDAC1, but they have limited ability to penetrate cancer cell membranes due to poor permeability
Solution Approach 1:
The patent merges two functional components: the VDAC1-targeting peptide sequence and cell-penetrating peptide sequences. This combination allows the conjugate to first penetrate the cancer cell membrane via the CPP component, then deliver the VDAC1-targeting portion to its destination, thereby achieving both permeability and apoptosis induction effectiveness.
Solution Approach 2:
The cell-penetrating peptide acts as an intermediary that facilitates the entry of the VDAC1-targeting peptide into the cancer cell. The CPP component mediates membrane translocation, allowing the therapeutic payload (VDAC1-targeting peptide) to reach its intracellular target effectively.
3Reliability
If cancer cells overexpress anti-apoptotic proteins like HK-I, then they develop resistance to chemotherapy and peptide-based therapies, but this resistance mechanism can be overcome by specific peptide design
Solution Approach 1:
The patent extracts the essential apoptotic induction function by focusing on a specific peptide sequence that targets VDAC1, bypassing the need to overcome multiple resistance mechanisms simultaneously. By concentrating on a single critical target (VDAC1) rather than attempting to inhibit multiple anti-apoptotic proteins, the design simplifies the approach while maintaining effectiveness against resistant cancer cells.
Data Source
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AI summary
The present invention relates to short peptides based on the amino acids sequence of the N-terminal domain of the human mitochondrial protein voltage-dependent anion channel 1 (VDAC) and to peptide conjugates further comprising a cell permeability enhancing moiety. The peptides, peptide conjugates and pharmaceutical composition comprising same are useful for treating diseases characterized by cell hyperproliferation or resistance to cell death, particularly cancer.