NGR Peptide Conjugate Stability via N-Terminal Modification
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Solution Overview
Problem
The instability and molecular heterogeneity of CNGRCG-cytokine conjugates, such as NGR-TNF, due to post-translational modification reactions pose challenges in drug manufacturing, storage, and pharmacological/toxicological implications, limiting their efficacy and safety for cancer therapy.
Innovation Solution
A conjugate comprising a CNGRCG peptide linked to the N-terminus of a protein, with an additional serine residue (S-NGR-TNF) or a different N-terminal sequence, to enhance stability and homogeneity, allowing for improved binding affinity to CD13 and antitumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If CNGRCG peptide is conjugated to cytokine to target tumor vessels, then tumor targeting capability is improved, but molecular stability and homogeneity deteriorate due to post-translational modifications
Solution Approach 1:
The patent modifies the N-terminal sequence parameters of the CNGRCG peptide by introducing a serine residue at position 1 (changing sequence to SCNGRCG) and using alternative N-terminal sequences (acetylated CNGRCG, O-propyl CNGRCG). These parameter changes in the amino acid sequence prevent unwanted post-translational modifications while preserving CD13 binding capability, thus resolving the contradiction between targeting capability and molecular stability.
Solution Approach 2:
The patent applies local quality modification by specifically altering only the N-terminal region of the CNGRCG peptide (positions 1-2) while leaving the core CNGRCG sequence intact. This localized modification at the N-terminus prevents heterogeneous modifications without affecting the tumor targeting function mediated by the CD13-binding region.
2Reliability
If CNGRCG-cytokine conjugate is used for cancer therapy, then antitumor activity is improved, but systemic toxicity increases
Solution Approach 1:
By changing the N-terminal sequence parameters (introducing serine, acetylation, or O-propyl groups), the patent creates conjugates with improved stability and homogeneity that maintain targeted delivery to tumor vessels. This reduces off-target effects and systemic toxicity while preserving the antitumor activity of the cytokine component.
3Ease of manufacture
If standard CNGRCG conjugate is manufactured, then production is simplified, but manufacturing precision and homogeneity deteriorate due to unwanted modification reactions
Solution Approach 1:
The patent changes the N-terminal sequence parameters to SCNGRCG or uses chemically modified versions (acetylated, O-propyl). These parameter changes prevent heterogeneous modifications during manufacturing and storage, enabling production of homogeneous conjugates with defined molecular weight and structure, thus improving manufacturing precision without significantly complicating the production process.
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 modified conjugate, S-NGR-TNF, demonstrates increased stability, homogeneity, and potent antitumor activity, reducing systemic toxicity and enhancing the therapeutic index when used alone or in combination with chemotherapy.
Implementation Method 1
a cyclic disulfide-bridged peptide containing NGR (CNGRC (SEQ ID NO:5)) can specifically recognize vessels expressing aminopeptidase N (CD13)
Implementation Method 2
tumor necrosis factor-α (TNF), a cytokine capable of altering the endothelial barrier function and promoting chemotherapeutic drug penetration/ immune cell infiltration in tumor tissues
Data Source
AI summary
The present invention relates to a conjugate comprising a first peptide of sequence CNGRCG (SEQ ID NO: 1) linked to the N-terminus of a protein and a compound X linked to the N-terminus of said peptide and to related medical uses.