An N-capping asparagine–lysine–proline (NKP) motif contributes to a hybrid flexible/stable multifunctional peptide scaffold

Cardoso, Marlon Henrique; Chan, Lai Yue; Cândido, Elizabete de Souza; Buccini, Danieli Fernanda; Rezende, Samilla B.; Torres, Marcelo Der Torossian; Oshiro, Karen G. N.; Silva, Ítala C.; Gonçalves, Sónia; Lu, Timothy K.; Santos, Nuno C.; Fuente-Núñez, César de la; Craik, David J.; Franco, Octávio L.

doi:10.1039/d1sc06998e

Cited by 3 publications

(7 citation statements)

References 48 publications

(81 reference statements)

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“…Here, we observed similar behavior, and through the NMR results we found that mastoparan-R1 and mastoparan-R4 adopt an a-helix structure; other studies have also reported that peptides of this class have a tendency for this environment-dependent structural organization [11,12,31]. Factors such as sequence symmetry, residue distribution, flexibility, and secondary structure may be beneficial to increase antimicrobial activity and decrease cytotoxicity, improve selectivity, and stability [19,28,32,33]. Mohanram et al [34] designed an AMP called RR12 with cationic and hydrophobic characteristics with 12 residues distributed in such a way as to obtain a well-defined polar and nonpolar face, demonstrating a predominant amphipathic character and two parent peptides with specific modifications, namely the substitution of Arg5 by Trp5 and another which substitution of Trp5 by Ile7 [34].…”

Section: Structural Analysissupporting

confidence: 83%

“…Factors such as sequence symmetry, residue distribution, flexibility, and secondary structure may be beneficial to increase antimicrobial activity and decrease cytotoxicity, improve selectivity, and stability [19,28,32,33]. Mohanram et al.…”

Section: Resultsmentioning

confidence: 99%

“…Characteristics such as helicity, hydrophobicity, and hydrophobic moment can affect the salt-tolerance and antimicrobial activity of a-helical AMPs [18,19]. Park and co-workers [18] tested different peptides with RLLR repeats, suggesting that structural instability may interfere with electrostatic interactions and, therefore, could be responsible for salt sensitivity in AMPs.…”

Section: Antimicrobial Kinetic Activities For Mastoparan-l Mastoparan...mentioning

confidence: 99%

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Deciphering the structure and mechanism of action of computer‐designed mastoparan peptides

Oshiro,

Freitas,

Rezende

et al. 2023

The FEBS Journal

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Mastoparans are cationic peptides with multifunctional pharmacological properties. Mastoparan‐R1 and mastoparan‐R4 were computationally designed based on native mastoparan‐L from wasps and have improved therapeutic potential for the control of bacterial infections. Here, we evaluated whether these peptides maintain their activity against Escherichia coli strains under a range of salt concentrations. We found that mastoparan‐R1 and mastoparan‐R4 preserved their activity under the conditions tested, including having antibacterial activities at physiological salt concentrations. The overall structure of the peptides was investigated using circular dichroism spectroscopy in a range of solvents. No significant changes in secondary structure were observed (random coil in aqueous solutions and α‐helix in hydrophobic and anionic environments). The three‐dimensional structures of mastoparan‐R1 and mastoparan‐R4 were elucidated through nuclear magnetic resonance spectroscopy, revealing amphipathic α‐helical segments for Leu3‐Ile13 (mastoparan‐R1) and Leu3‐Ile14 (mastoparan‐R4). Possible membrane‐association mechanisms for mastoparan‐R1 and mastoparan‐R4 were investigated through surface plasmon resonance and leakage studies with synthetic POPC and POPC/POPG (4:1) lipid bilayers. Mastoparan‐L had the highest affinity for both membrane systems, whereas the two analogs had weaker association, but improved selectivity for lysing anionic membranes. This finding was also supported by molecular dynamics simulations, in which mastoparan‐R1 and mastoparan‐R4 were found to have greater interactions with bacteria‐like membranes compared with model mammalian membranes. Despite having a few differences in their functional and structural profiles, the mastoparan‐R1 analog stood out with the highest activity, greater bacteriostatic potential, and selectivity for lysing anionic membranes. This study reinforces the potential of mastoparan‐R1 as a drug candidate.

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Section: Structural Analysissupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Antimicrobial Kinetic Activities For Mastoparan-l Mastoparan...mentioning

confidence: 99%

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Deciphering the structure and mechanism of action of computer‐designed mastoparan peptides

Oshiro,

Freitas,

Rezende

et al. 2023

The FEBS Journal

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“…When applied at 16 μm (twice the MIC against planktonic P. aeruginosa), the peptide PaDBS1R7 (PMARNKPKILKRILAKIFK-NH 2 ) was able to eradicate 2 d old P. aeruginosa biofilms in flow chambers [171]. Moreover, this peptide was applied in a skin abscess mouse model at 64 μm, where it was able to reduce the bacterial burden by a factor of 100 to >1000 four days after treatment with a single dose of peptide [171]. In addition to reducing the bacterial load, this peptide showed immunomodulatory activity facilitating a quick recovery from the infection [171].…”

Section: Anti-biofilm Activitymentioning

confidence: 99%

A guided tour through α-helical peptide antibiotics and their targets

2023

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Nowadays, not only biologists, but also researchers from other disciplines such as chemistry, pharmacy, material sciences, or physics are working with antimicrobial peptides. This review is written for researchers and students working in or interested in the field of antimicrobial peptides – and especially those who do not have a profound biological background. To lay the ground for a thorough discussion on how AMPs act on cells, the architectures of mammalian and bacterial cell envelopes are described in detail because they are important targets of AMPs and provide the basis for their selectivity. The modes of action of α-helical AMPs (αAMPs) are not limited to different models of membrane permeabilization, but also include the disruption of intracellular processes, as well as the formation of fibrillary structures and their potential implications for antimicrobial activity. As biofilm-related infections are very difficult to treat with conventional antibiotics, they pose a major problem in the clinic. Therefore, this review also discusses the biological background of biofilm infections and the mode of actions of αAMPs against biofilms. The last chapter focusses on the design of αAMPs by providing an overview of historic milestones in αAMP design. It describes how modern αAMP design is aiming to produce peptides suitable to be applied in the clinic. Hence, the article concludes with a section on translational research discussing the prospects of αAMPs and remaining challenges on their way into the clinic.

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“…Antimicrobial peptides and antifungal peptides (both denoted AMP) , are considered a new weapon against antibiotic-resistant microorganisms. − AMPs usually form helical or layered structures with separate hydrophilic and hydrophobic faces, which is also referred to as facial amphiphilicity. This specific amphiphilic structure allows most of the AMPs to electrostatically bind to the negatively charged bacterial membrane and leads to cell death. − Moreover, the physical destruction of the cell membrane makes it difficult for microorganisms to produce drug resistance. − Therefore, a lot of effort has been put forward to develop AMP-based fungicides that have shown very promising applications. − …”

Section: Introductionmentioning

confidence: 99%

Noncovalent Bile Acid Oligomers as Facial Amphiphilic Antimicrobials

et al. 2022

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New antimicrobial agents are needed to address the ever-growing risk of bacterial resistance, particularly for methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus). Here, we report a class of bile acid oligomers as facial amphiphilic antimicrobials, which are noncovalently fabricated by cholic acid (CA) and deoxycholic acid (DCA) with polyamines (e.g., diamines, diethylenetriamine, spermidine, and spermine). The antibacterial activities of these bile acid oligomers (CA/polyamines and DCA/polyamines) against S. aureus become stronger with increasing the amine group numbers of polyamines without obviously enhanced cytotoxicity and skin irritation. DCA/spermine, entirely composed of natural products, exhibits the best antibacterial activity but the lowest cytotoxicity and the weakest skin irritation. All CA/polyamines and DCA/polyamines form well-ordered ribbon-like aggregates, collecting numerous facial amphiphilic structures to significantly enhance the interactions with bacterial membranes. In particular, the biogenic polyamines with more than two amine groups provide extra positively charged sites, hence facilitating the binding of bile acid oligomers to the negatively charged outer membrane of the bacteria via electrostatic interaction. This in turn promotes more oligomeric bile acid units that can be inserted into the membrane through hydrophobic interaction between bile acids and lipid domains. The noncovalently constructed and separable amphiphilic antimicrobials can avoid the long-term coexistence of microorganisms and antibacterial molecules in different acting modes. Therefore, the noncovalent bile acid oligomers, especially those with higher oligomerization degrees, can be a potential approach to effectively enhance antibacterial activity, improve environmental friendliness, and reduce bacterial drug resistance.

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An N-capping asparagine–lysine–proline (NKP) motif contributes to a hybrid flexible/stable multifunctional peptide scaffold

Abstract: An unusual N-capping asparagine-lysine-proline (5NKP7) motif yields a coil/N-cap/α-helix multifunctional scaffold in a computer-made peptide selective for anionic surfaces and with anticancer, antibacterial, antibiofilm, anti-infective (in vivo), and immunomodulatory potential.

Cited by 3 publications

References 48 publications

Deciphering the structure and mechanism of action of computer‐designed mastoparan peptides

Deciphering the structure and mechanism of action of computer‐designed mastoparan peptides

A guided tour through α-helical peptide antibiotics and their targets

Noncovalent Bile Acid Oligomers as Facial Amphiphilic Antimicrobials

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