インサイト - Computational Biology - # Antimicrobial Peptides from Heparin-Binding Proteins

Heparin-Binding Proteins as a Source of Potent Antimicrobial Peptides Targeting Gram-Negative Bacteria

Q: How could the structural insights gained from this study be leveraged to further optimize the antimicrobial potency and selectivity of HBP-derived peptides?

The structural insights obtained from this study, particularly regarding the presence of a CPC’ clip motif in HBPs that is essential for binding both heparin and LPS, provide a foundation for further optimizing the antimicrobial potency and selectivity of HBP-derived peptides. One key aspect would be to focus on enhancing the interactions between the peptides and their targets, heparin, and LPS, by specifically targeting and modifying the CPC’ motif. By fine-tuning the amino acid composition and spatial arrangement of this motif, it may be possible to increase the binding affinity of the peptides to both heparin and LPS, thereby improving their antimicrobial activity. Additionally, the structural characterization of the peptides in different conditions, such as in the presence of heparin analogs or LPS, can guide the design of peptide analogs with enhanced structural stability and activity. By studying the conformational changes that occur upon interaction with these molecules, researchers can identify key structural features that contribute to antimicrobial activity and use this information to design more potent and selective peptides. Furthermore, leveraging computational tools and molecular modeling techniques to predict and optimize the interactions between the peptides and their targets can aid in the rational design of novel HBP-derived antimicrobial peptides. By simulating the peptide-target interactions and predicting the binding affinities of designed peptides, researchers can prioritize the synthesis and testing of the most promising candidates, leading to the development of optimized antimicrobial agents with improved efficacy and specificity.

Q: What other classes of host defense proteins beyond HBPs might also contain cryptic antimicrobial peptides that could be mined for novel antibacterial agents?

Beyond HBPs, various classes of host defense proteins are likely to contain cryptic antimicrobial peptides that could be explored for the development of novel antibacterial agents. One such class is cationic antimicrobial peptides (AMPs) that are known to play a crucial role in the innate immune response against pathogens. These peptides are often found in various tissues and secretions of animals and humans, where they exert antimicrobial activity by targeting and disrupting the membranes of bacteria. Another class of proteins that may harbor cryptic AMPs is protease enzymes. Proteases are involved in various physiological processes, including inflammation and wound healing, and some proteases have been found to generate antimicrobial peptides upon proteolytic cleavage of specific protein substrates. By identifying and characterizing these cryptic AMPs within protease enzymes, researchers can uncover novel antibacterial agents with unique mechanisms of action. Furthermore, proteins involved in the complement system, such as complement proteins C3 and C5, are also potential candidates for containing cryptic antimicrobial peptides. These proteins play a central role in the immune response and have been shown to possess antimicrobial properties. By investigating the proteolytic processing of complement proteins and identifying the AMPs generated during this process, researchers can discover new antibacterial agents for therapeutic applications. Overall, exploring a wide range of host defense proteins beyond HBPs for the presence of cryptic AMPs holds great potential for uncovering novel antibacterial agents with diverse structures and activities that can combat antibiotic-resistant pathogens.

Q: Given the potential dual roles of HBPs in both immune defense and coagulation, how might the interplay between these functions influence the in vivo efficacy and therapeutic applications of HBP-derived antimicrobial peptides?

The interplay between the immune defense and coagulation functions of HBPs can have significant implications for the in vivo efficacy and therapeutic applications of HBP-derived antimicrobial peptides. One key aspect to consider is the potential for crosstalk between the immune response and coagulation pathways, where the activation of one pathway may influence the activity of the other. In the context of antimicrobial peptides derived from HBPs, this interplay could impact the overall immune response to bacterial infections and the regulation of coagulation processes. The dual roles of HBPs in immune defense and coagulation suggest that HBP-derived antimicrobial peptides may have multifaceted effects in vivo. For example, these peptides may not only target and eliminate bacterial pathogens but also modulate immune responses and inflammatory processes. By interacting with immune cells and modulating cytokine production, HBP-derived peptides could potentially enhance the host's ability to combat infections while also regulating excessive inflammation. Furthermore, the involvement of HBPs in coagulation pathways raises the possibility that HBP-derived antimicrobial peptides may influence blood clotting and thrombosis. Understanding the interplay between the immune defense and coagulation functions of HBPs is crucial for assessing the potential risks and benefits of using HBP-derived peptides as antimicrobial agents. Careful consideration of the effects of these peptides on coagulation parameters and immune responses is essential for the safe and effective therapeutic application of HBP-derived antimicrobial peptides in clinical settings. Overall, the intricate relationship between the immune defense and coagulation functions of HBPs underscores the importance of evaluating the in vivo efficacy and potential side effects of HBP-derived antimicrobial peptides in preclinical and clinical studies to ensure their safety and efficacy as novel antibacterial agents.

核心概念

Heparin-binding proteins contain cryptic antimicrobial peptides that selectively target and kill gram-negative bacteria by binding to and disrupting their cell walls.

要約

The study investigates the hypothesis that heparin-binding proteins (HBPs) can also bind to and recognize the lipopolysaccharides (LPS) in the cell walls of gram-negative bacteria, and that these HBPs may contain cryptic antimicrobial peptide (AMP) regions that can selectively target and kill gram-negative bacteria.

The key findings are:

Using computational tools, the authors identified potential antimicrobial regions in 82% of HBPs, and found that these regions often colocalize with the heparin-binding sites containing a conserved CPC' motif.
The authors synthesized five peptides (HBP1-5) derived from these predicted antimicrobial regions and found that they exhibited strong binding affinity for both heparin and LPS, as well as potent antimicrobial activity against gram-negative bacteria like E. coli, A. baumannii, and P. aeruginosa, while being much less active against gram-positive bacteria.
Mechanistic studies showed that the HBP-derived peptides, especially HBP-4 and HBP-5, can effectively bind to and disrupt the bacterial cell wall and membrane, leading to rapid cell death.
Structural characterization revealed that binding to heparin or LPS triggers a conformational change in the peptides, promoting a more defined structure that is critical for their antimicrobial activity.
Among the peptides tested, HBP-5 emerged as the most promising candidate, exhibiting potent and selective antimicrobial activity against gram-negative bacteria, including multidrug-resistant strains, while showing low hemolytic and cytotoxic effects.

The results suggest that HBPs represent a valuable source of a new class of antimicrobial peptides that can selectively target and kill gram-negative bacteria, which are a major concern due to the rise of antibiotic resistance.

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biorxiv.org

統計

The peptides HBP-4 and HBP-5 exhibited the strongest binding affinity for both heparin and LPS.
HBP-4 and HBP-5 showed the highest antimicrobial activity against gram-negative bacteria, with MIC values in the nanomolar range.
HBP-5 displayed the highest selectivity ratio (LC50/MIC) between 50 and 800, indicating outstanding antimicrobial activity with low cytotoxicity.

引用

"HBPs therefore represent a source for new antimicrobials effective against antibiotic-resistant pathogens."
"HBP-5 emerges as the most attractive analog, with a selectivity ratio (LC50/MIC) between 50 and 800 (depending on bacterial strain) that must be regarded as outstanding for AMPs."

抽出されたキーインサイト

Mining the heparinome for cryptic antimicrobial peptides that selectively kill gram-negative bacteria

by Sandin Garci... 場所 www.biorxiv.org 10-22-2023

https://www.biorxiv.org/content/10.1101/2023.10.19.563059v2

深掘り質問

How could the structural insights gained from this study be leveraged to further optimize the antimicrobial potency and selectivity of HBP-derived peptides?

The structural insights obtained from this study, particularly regarding the presence of a CPC’ clip motif in HBPs that is essential for binding both heparin and LPS, provide a foundation for further optimizing the antimicrobial potency and selectivity of HBP-derived peptides. One key aspect would be to focus on enhancing the interactions between the peptides and their targets, heparin, and LPS, by specifically targeting and modifying the CPC’ motif. By fine-tuning the amino acid composition and spatial arrangement of this motif, it may be possible to increase the binding affinity of the peptides to both heparin and LPS, thereby improving their antimicrobial activity.
Additionally, the structural characterization of the peptides in different conditions, such as in the presence of heparin analogs or LPS, can guide the design of peptide analogs with enhanced structural stability and activity. By studying the conformational changes that occur upon interaction with these molecules, researchers can identify key structural features that contribute to antimicrobial activity and use this information to design more potent and selective peptides.
Furthermore, leveraging computational tools and molecular modeling techniques to predict and optimize the interactions between the peptides and their targets can aid in the rational design of novel HBP-derived antimicrobial peptides. By simulating the peptide-target interactions and predicting the binding affinities of designed peptides, researchers can prioritize the synthesis and testing of the most promising candidates, leading to the development of optimized antimicrobial agents with improved efficacy and specificity.

What other classes of host defense proteins beyond HBPs might also contain cryptic antimicrobial peptides that could be mined for novel antibacterial agents?

Beyond HBPs, various classes of host defense proteins are likely to contain cryptic antimicrobial peptides that could be explored for the development of novel antibacterial agents. One such class is cationic antimicrobial peptides (AMPs) that are known to play a crucial role in the innate immune response against pathogens. These peptides are often found in various tissues and secretions of animals and humans, where they exert antimicrobial activity by targeting and disrupting the membranes of bacteria.
Another class of proteins that may harbor cryptic AMPs is protease enzymes. Proteases are involved in various physiological processes, including inflammation and wound healing, and some proteases have been found to generate antimicrobial peptides upon proteolytic cleavage of specific protein substrates. By identifying and characterizing these cryptic AMPs within protease enzymes, researchers can uncover novel antibacterial agents with unique mechanisms of action.
Furthermore, proteins involved in the complement system, such as complement proteins C3 and C5, are also potential candidates for containing cryptic antimicrobial peptides. These proteins play a central role in the immune response and have been shown to possess antimicrobial properties. By investigating the proteolytic processing of complement proteins and identifying the AMPs generated during this process, researchers can discover new antibacterial agents for therapeutic applications.
Overall, exploring a wide range of host defense proteins beyond HBPs for the presence of cryptic AMPs holds great potential for uncovering novel antibacterial agents with diverse structures and activities that can combat antibiotic-resistant pathogens.

Given the potential dual roles of HBPs in both immune defense and coagulation, how might the interplay between these functions influence the in vivo efficacy and therapeutic applications of HBP-derived antimicrobial peptides?

The interplay between the immune defense and coagulation functions of HBPs can have significant implications for the in vivo efficacy and therapeutic applications of HBP-derived antimicrobial peptides. One key aspect to consider is the potential for crosstalk between the immune response and coagulation pathways, where the activation of one pathway may influence the activity of the other. In the context of antimicrobial peptides derived from HBPs, this interplay could impact the overall immune response to bacterial infections and the regulation of coagulation processes.
The dual roles of HBPs in immune defense and coagulation suggest that HBP-derived antimicrobial peptides may have multifaceted effects in vivo. For example, these peptides may not only target and eliminate bacterial pathogens but also modulate immune responses and inflammatory processes. By interacting with immune cells and modulating cytokine production, HBP-derived peptides could potentially enhance the host's ability to combat infections while also regulating excessive inflammation.
Furthermore, the involvement of HBPs in coagulation pathways raises the possibility that HBP-derived antimicrobial peptides may influence blood clotting and thrombosis. Understanding the interplay between the immune defense and coagulation functions of HBPs is crucial for assessing the potential risks and benefits of using HBP-derived peptides as antimicrobial agents. Careful consideration of the effects of these peptides on coagulation parameters and immune responses is essential for the safe and effective therapeutic application of HBP-derived antimicrobial peptides in clinical settings.
Overall, the intricate relationship between the immune defense and coagulation functions of HBPs underscores the importance of evaluating the in vivo efficacy and potential side effects of HBP-derived antimicrobial peptides in preclinical and clinical studies to ensure their safety and efficacy as novel antibacterial agents.