Macrocyclic Peptides Modulating TNF Alpha
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Solution Overview
Problem
Current treatments for inflammatory and autoimmune disorders related to TNFα activity have limitations in terms of stability, bioavailability, therapeutic index, and toxicity, necessitating the development of new modulators.
Innovation Solution
The development of a new class of macrocyclic peptides that act as effective inhibitors of TNFα activity, offering improved stability, bioavailability, therapeutic index, and reduced toxicity compared to existing agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If protein-based therapeutic agents (antibodies, etanercept) are used to inhibit TNFα binding to TNFR1 and TNFR2, then TNFα activity is effectively blocked, but stability and bioavailability are limited
Solution Approach 1:
The patent applies parameter changes by transitioning from protein-based therapeutics to peptide-based compounds, fundamentally altering the chemical composition parameters. The macrocyclic peptide structure with specific amino acid sequences and cyclic constraints modifies physical-chemical properties including stability, bioavailability, and pharmacokinetic profile while maintaining TNFα binding capability
Solution Approach 2:
The invention employs composite material principles by creating macrocyclic peptides that combine multiple amino acid residues in specific sequences with cyclic structural elements. This composite structure integrates the benefits of peptide flexibility with the stability of cyclic conformations, achieving improved pharmacological properties compared to linear peptides or protein antibodies
2Adaptability or versatility
If protein-based therapeutic agents are used to modulate TNFα activity, then inflammatory and autoimmune disorders are treated, but toxicity and therapeutic index are suboptimal
Solution Approach 1:
The patent utilizes parameter changes by modifying the molecular size, charge distribution, and structural rigidity through macrocyclization. These parameter modifications result in altered tissue distribution, reduced off-target effects, and improved therapeutic index while maintaining broad applicability across multiple inflammatory and autoimmune conditions
3Reliability
If new macrocyclic peptides are developed to improve stability and bioavailability, then therapeutic index is enhanced, but device complexity and manufacturing complexity increase
Solution Approach 1:
The patent applies segmentation by dividing the peptide chain into specific amino acid sequences that are then cyclized. This segmentation allows for modular design where different amino acid sequences can be combined and optimized independently, facilitating structure-activity relationship studies and rational drug design despite the complex macrocyclic structure
Solution Approach 2:
The invention employs parameter changes through controlled macrocyclization that introduces specific structural constraints. By adjusting parameters such as ring size, amino acid composition, and disulfide bridge placement, the patent optimizes the balance between molecular complexity and therapeutic performance, achieving enhanced stability without excessive complexity
Data Source
AI summary
Disclosed are macrocyclic peptide compounds or a salt thereof, which are useful as modulators of TNFα, and pharmaceutical compositions comprising such compounds. These compounds may be useful in treating cancers, inflammatory and autoimmune diseases.