APIM Peptides Target PCNA to Disrupt Microbial DNA Replication
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Solution Overview
Problem
Current antimicrobial therapies face challenges due to the development of multidrug-resistant microbial strains, particularly in bacterial infections, where existing antibiotics often fail to effectively target DNA replication and repair mechanisms, leading to difficulties in treating infections and combating biofilms.
Innovation Solution
The use of APIM peptides, which interact with PCNA proteins in microbial cells, disrupting DNA replication and repair processes, thereby exerting direct cytotoxic effects and sensitizing cells to other antimicrobial agents, and potentially inhibiting biofilm formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antibiotics are used to treat bacterial infections, then common infections can be effectively targeted, but multidrug-resistant microbial strains develop and existing antibiotics fail
Solution Approach 1:
The patent uses APIM peptides as intermediary agents that bind to PCNA proteins in microbial cells, disrupting DNA replication and repair processes. This intermediary mechanism targets a fundamental cellular process that is essential for microbial survival and resistance development, providing a new therapeutic approach that bypasses traditional antibiotic resistance mechanisms.
Solution Approach 2:
The invention changes the therapeutic parameter from targeting cell wall synthesis or protein synthesis (traditional antibiotics) to targeting DNA replication and repair processes through PCNA interaction. This parameter change in the mechanism of action allows the treatment to be effective against multidrug-resistant strains that have developed resistance to conventional antibiotics.
2Reliability
If peptides containing PIP-box are used to interact with PCNA, then DNA replication and repair can be targeted, but extreme cytotoxicity to human and animal cells occurs
Solution Approach 1:
The patent modifies the peptide sequence to create an APIM motif with specific local quality characteristics that differ from the canonical PIP-box. The APIM motif (X1X2X3X4X5 where X1 is basic, X2 is aromatic, X3 is uncharged non-aromatic, X4 is non-proline/non-acidic/non-aromatic, X5 is basic or proline) provides selective interaction with microbial PCNA while reducing affinity for human PCNA, thereby achieving local specificity that reduces cytotoxicity to human cells.
Solution Approach 2:
The invention changes the binding affinity parameter between the peptide and PCNA protein. By modifying the amino acid sequence from canonical PIP-box to APIM motif, the peptide maintains sufficient binding affinity to disrupt microbial DNA replication and repair processes, while the altered parameters reduce binding to human PCNA, thereby reducing cytotoxicity to human and animal cells.
3Adaptability or versatility
If traditional antibiotics are used, then common bacterial infections can be treated, but they fail to effectively target DNA replication and repair mechanisms and cannot combat biofilms
Solution Approach 1:
The APIM peptide targets a fundamental cellular process (DNA replication and repair through PCNA interaction) that is universal across different microbial types including bacteria and fungi, and is essential for both planktonic and biofilm states. This universal targeting mechanism provides multi-functionality that allows the treatment to be effective against a broad range of infections and microbial forms, including those resistant to traditional antibiotics.
Data Source
AI summary
The present invention provides an agent, or a composition containing an agent, for use in treating or preventing a bacterial infection in a subject, wherein said agent comprises:(i) an oligopeptidic compound comprising a PCNA interacting motif and a domain that facilitates the cellular uptake of said compound,wherein the PCNA interacting motif is X1X2X3X4X5 (SEQ ID NO: 1) andwherein:X1 is a basic amino acid;X2 is an aromatic amino acid;X3 is an uncharged amino acid other than an aromatic amino acid, Glycine (G) and Proline (P);X4 is any amino acid other than Proline (P), an acidic amino acid or an aromatic amino acid; andX5 is a basic amino acid or Proline (P); or(ii) a nucleic acid molecule comprising a sequence encoding the oligopeptidic compound of (i).In certain aspects the agent and compositions of the invention may be used as single agents. In other aspects of the invention agents and compositions of the invention may be used in conjunction with one or more additional active agents, such as antibiotics.