DAGRS Peptides Target Oncogenes With Reduced Toxicity
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Solution Overview
Problem
Current cancer treatments lack selectivity, leading to severe side effects and toxicity, as they are not specific to cancer cells, and existing targeted therapies face challenges with bioavailability and safety, particularly in treating recurrent cancers.
Innovation Solution
Development of synthetic, genetically engineered Directed Antagonists to cancer Growth Signals (DAGRS) that can be targeted against any oncogene, utilizing a unique peptide arrangement for high affinity binding and membrane translocation, reducing toxicity by humanizing the Tat protein and removing toxic domains, thereby enhancing bioavailability and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If current cancer treatments (chemotherapy, radiation, surgery) are used, then cancer cells are targeted, but normal cells are also damaged causing severe side effects and toxicity
Solution Approach 1:
The invention segments the treatment approach by using modular peptide constructs (DAGRS) that can be individually designed to target specific oncogenes. Each peptide is a discrete unit that can be synthesized and administered separately, allowing precise targeting without affecting other cellular pathways. This segmentation enables selective cancer cell targeting while sparing normal cells.
Solution Approach 2:
The DAGRS peptides act as intermediaries that bridge the gap between normal physiological processes and cancer treatment. These peptides mimic natural signal-transducing peptides but are engineered to specifically bind to and inhibit oncogenic proteins, thereby mediating selective cancer cell death without directly damaging normal cells. The intermediary nature of these peptides allows for precise control of the therapeutic effect.
2Ease of manufacture
If targeted therapies are developed to improve selectivity, then normal cells are spared, but bioavailability and safety challenges remain particularly for recurrent cancers
Solution Approach 1:
The invention changes the parameters of peptide design by using reverse-phase high-performance liquid chromatography (RP-HPLC) purification to achieve greater than 95% purity. This parameter change in purification efficiency directly improves bioavailability by ensuring that the administered peptide is free from contaminants that could cause toxicity. The controlled synthesis and purification parameters allow for consistent, reliable delivery of the therapeutic peptide.
Solution Approach 2:
The DAGRS peptides are designed as simplified copies or mimics of natural signal-transducing peptides. Rather than using complex viral vectors or whole proteins, the invention creates streamlined peptide versions that retain the essential binding and inhibitory functions. This copying approach improves safety by eliminating unnecessary complex components that could cause adverse reactions while maintaining the core therapeutic mechanism.
3Ease of manufacture
If existing targeted therapies are used, then specific oncogenes are inhibited, but resistance mechanisms develop in recurrent cancers
Solution Approach 1:
The DAGRS platform provides universal applicability by being designed to target multiple different oncogenes. The modular peptide structure allows the same basic framework to be adapted for inhibiting various oncogenic proteins by simply changing the binding region. This multi-functionality ensures that if resistance develops to one target, alternative DAGRS peptides can be used against different oncogenes, maintaining therapeutic effectiveness against recurrent and resistant cancers.
Data Source
AI summary
The present invention describes a unique method of treating cancer with the administration of an improved DAGRS™ construct which functions as a humanized agent specifically targeting cancer cells in vivo. A specific DAGRS™ is described constructed of a humanized drug delivery biologic, carboxyl to an Apoptin fragment consisting of Apoptin's proline-rich SH3-binding fragment, a spacer, and a MAP kinase (MAPK) phosphorylation site, in replacement of the SH3-binding domain at HIV-1 TAT's amino terminus. Apoptin is a viral protein with incumbent immunogenicity and toxicity in humans. Improved DAGRS™ constructs are described that replace the viral VP3 peptide with human AKT peptide or derivative, all equivalently spaced 11 amino acids from the initial proline to the beginning of the MAPK phosphorylation site, through which technology the DAGRS™ is fully humanized. DAGRS™ provide for improved bioavailability, enhanced specific activity, and low toxicity for in vivo treatment of cancer. DAGRS™ are a superior method for targeting any oncogene with an inhibitory peptide.An algorithm for “humanization” is described through which human functional equivalent(s) to viral product(s) are identified by alignment of peptides anchored at each end by matching functional motifs that are spaced equivalently distant in the two aligned peptides. The algorithm totally disregards the primary amino acid composition of the spacer, and as such separates from current computer algorithms that prioritize primary amino acid alignments. Accounting for spacing dictates that functional domains be oriented correctly in three dimensions. The invention taught here can be developed into computer algorithms for rapidly identifying these anchored alignments, and thereafter developing safe humanized drugs from disruptive viral activities. Computers once taught the basic rules for anchoring equivalents, can improve on the basic algorithm through artificial intelligence to expand drug development.