Cyclic Cell-Penetrating Peptides for Multidrug-Resistant Gonococcal Infections
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Solution Overview
Problem
The rise of multidrug-resistant Neisseria gonorrhoeae strains has rendered existing antibiotics ineffective, and there is a lack of vaccines, making gonococcal infections a significant public health threat, with increased transmission of HIV and challenging control measures.
Innovation Solution
Development of cyclic cell-penetrating peptides (CPPs) with cyclic structures, such as those comprising 6-aminohexanoic-spaced oligoarginine sequences like CRXRRXRRXRRXRC and RXRRXRRXRRXRC, which are bactericidal for gonococci, reduce cytokine induction in human cells, and are non-cytotoxic, offering increased potency and selectivity over linear CPPs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If linear CPPs are used to treat gonococcal infections, then some bactericidal activity is achieved, but potency is insufficient against multidrug-resistant strains
Solution Approach 1:
The patent applies parameter changes by modifying the structural parameters of CPPs - specifically transitioning from linear to cyclic configurations and incorporating specific amino acid sequences (e.g., R5K, R6K, R7K motifs with 6-aminohexanoic acid spacers). These parameter modifications result in significantly enhanced bactericidal potency against MDR gonococcal strains, with cyclic CPPs demonstrating minimum bactericidal concentrations 10-100 times lower than linear counterparts.
Solution Approach 2:
The patent employs composite material principles by creating hybrid peptide structures that combine cationic arginine residues with 6-aminohexanoic acid spacers in specific patterns. These composite CPP sequences (such as CRXRRXRRXRRXRC with disulfide bridges) integrate multiple functional elements - cell-penetrating capability, membrane-disrupting activity, and antibacterial potency - into a unified molecular structure that overcomes multidrug resistance.
2Reliability
If existing antibiotics are used to treat gonococcal infections, then treatment is effective for susceptible strains, but effectiveness is lost against multidrug-resistant strains
Solution Approach 1:
The patent converts the harmful multidrug resistance mechanism into a beneficial outcome by using cyclic CPPs with non-classical antibacterial mechanisms. These CPPs kill MDR gonococci through membrane disruption and cytoplasmic penetration rather than targeting traditional antibiotic pathways, thereby converting the resistance problem (bacteria surviving antibiotic exposure) into a benefit (bacteria being killed by CPPs regardless of prior antibiotic resistance).
Solution Approach 2:
The patent uses cyclic CPPs as intermediary agents that bridge the gap between host cells and MDR bacteria. These CPPs penetrate both host cell membranes and bacterial membranes, delivering cytotoxic effects directly to bacteria while minimizing host cell damage. The cyclic structure with specific amino acid compositions serves as an effective intermediary that overcomes the resistance barrier created by traditional antibiotics.
3Adaptability or versatility
If linear CPPs are used, then some selectivity is achieved, but potency and selectivity are insufficient compared to cyclic structures
Solution Approach 1:
The patent applies the spheroidality principle by transitioning from linear (straight-line) CPP structures to cyclic (curved/looped) structures. This curvature fundamentally changes the peptide's three-dimensional conformation, enabling better interaction with bacterial membranes. The cyclic configuration allows the peptide to form more stable complexes with membrane lipids and creates a pre-organized structure that enhances both potency (lower MBC) and selectivity (reduced hemolysis) simultaneously.
Data Source
AI summary
Disclosed herein are cyclic peptides having activity as cell penetrating peptides (CPPs). Disclosed are cyclic cell penetrating peptides (cCPPs) comprising one or more of the cell penetrating peptides disclosed herein. Disclosed are cCPPs comprising a 6-aminohexanoic-spaced oligoarginine. Disclosed are cCPPs comprising the amino acid sequence of CRXRRXRRXRRXRC (SEQ ID NO:1), wherein X is aminohexanoic acid. In some aspects, the cCPP comprises a disulfide bridge. Disclosed are cCPPs comprising the amino acid sequence of RXRRXRRXRRXRC (SEQ ID NO:2), wherein X is aminohexanoic acid. In some aspects, the cCPPs comprise a thioether bridge.