Unnatural amino acids: promising implications for the development of new antimicrobial peptides

Wang, Xiuhong; Yang, Xiubin; Wang, Qiaoe; Meng, Demei

doi:10.1080/1040841x.2022.2047008

Cited by 30 publications

(27 citation statements)

References 149 publications

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“…The poor resistance to gastric protein has always been an insurmountable obstacle in the clinical application of AMPs [ 39 ]. In our above experiments, we found that the antibacterial activity of Pleu was remarkably decreased after pepsin treatment, while the antibacterial activity of the modified peptide GK-4 showed no decrease after pepsin treatment.…”

Section: Resultsmentioning

confidence: 99%

Truncated Pleurocidin Derivative with High Pepsin Hydrolysis Resistance to Combat Multidrug-Resistant Pathogens

et al. 2022

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The global prevalence of antimicrobial resistance calls for the development of novel antimicrobial agents, particularly for these orally available drugs. Structural modifications of the natural antimicrobial peptides (AMPs) provide a straightforward approach to develop potent antimicrobial agents with high specificity and low toxicity. In this study, we truncated 11-amino-acids at the C-terminus of Pleurocidin, an AMP produced by Pleuronectes americanus, and obtained four peptide analogues termed GK-1, GK-2, GK-3 and GK-4. Minimum inhibitory concentration (MIC) tests showed that GK-1 obtained by direct truncation of Pleurocidin has no antibacterial activity, while GK-2, GK-3 and GK-4 show considerable antibacterial activity with Pleurocidin. Notably, GK-4 displays rapid bacteriostatic activity, great stability and low hemolysis, as well as enhanced hydrolytic resistance to pepsin treatment. Mechanistic studies showed that GK-4 induces membrane damage by interacting with bacterial membrane-specific components, dissipates bacterial membrane potential and promotes the generation of ROS. SEM and CD analysis further confirmed the ability of GK-4 to resist pepsin hydrolysis, which may be attributed to its stable helicity structure. Collectively, our findings reveal that GK-4 is a potential orally available candidate to treat infections caused by multidrug-resistant pathogens.

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Section: Resultsmentioning

confidence: 99%

Truncated Pleurocidin Derivative with High Pepsin Hydrolysis Resistance to Combat Multidrug-Resistant Pathogens

et al. 2022

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“…It is also possible to increase the enzymatic stability by replacing an amino acid residue with a non-proteinogenic amino acid [ 94 ]. The choice in this field is very wide [ 70 ] ( Figure 4 ): (i) D-amino acids, which are normally not recognized by enzymes [ 95 , 96 , 97 ]; (ii) N-methyl-α-amino acids (characterized by limited conformational freedom and the reduced ability to form both inter- and intra-molecular hydrogen bonds), which have often shown better pharmacological properties than the originals [ 98 ]; (iii) proteinogenic amino acid derivatives with a rigid structure, such as L-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-6-carboxylic acid (L-spinacine, Spi) or L-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (Tic) [ 99 ]; (iv) β-amino acids, which have a significant influence on the secondary structure of the peptide [ 22 ] and that can be distinguished in β 2 , β 3 , homologated (with an extra carbon atom) or isomeric (with the same number of carbon atoms—and therefore also the same molecular mass—of the original) [ 70 ]; (v) γ-amino acids, in which two carbon atoms separate the amino and carboxyl groups, characterized by a great conformational versatility and stability towards proteases [ 22 , 100 , 101 ]; (vi) α-substituted (normally alkylated) amino acids, or α,α-disubstituted glycines [ 102 ]; (vii) β-substituted α-amino acids, i.e., alkylated to β carbon and thus equipped with an additional asymmetry centre [ 103 ]; and (viii) proline analogues, where the formation of α-helices is hindered by the bending induced in the chain [ 104 ].…”

Section: How To Increase Enzymatic Stability and Bioavailabilitymentioning

confidence: 99%

Lights and Shadows on the Therapeutic Use of Antimicrobial Peptides

Bellotti

Remelli

2022

Molecules

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The emergence of antimicrobial-resistant infections is still a major concern for public health worldwide. The number of pathogenic microorganisms capable of resisting common therapeutic treatments are constantly increasing, highlighting the need of innovative and more effective drugs. This phenomenon is strictly connected to the rapid metabolism of microorganisms: due to the huge number of mutations that can occur in a relatively short time, a colony can “adapt” to the pharmacological treatment with the evolution of new resistant species. However, the shortage of available antimicrobial drugs in clinical use is also caused by the high costs involved in developing and marketing new drugs without an adequate guarantee of an economic return; therefore, the pharmaceutical companies have reduced their investments in this area. The use of antimicrobial peptides (AMPs) represents a promising strategy for the design of new therapeutic agents. AMPs act as immune defense mediators of the host organism and show a poor ability to induce antimicrobial resistance, coupled with other advantages such as a broad spectrum of activity, not excessive synthetic costs and low toxicity of both the peptide itself and its own metabolites. It is also important to underline that many antimicrobial peptides, due to their inclination to attack cell membranes, have additional biological activities, such as, for example, as anti-cancer drugs. Unfortunately, they usually undergo rapid degradation by proteolytic enzymes and are characterized by poor bioavailability, preventing their extensive clinical use and landing on the pharmaceutical market. This review is focused on the strength and weak points of antimicrobial peptides as therapeutic agents. We give an overview on the AMPs already employed in clinical practice, which are examples of successful strategies aimed at overcoming the main drawbacks of peptide-based drugs. The review deepens the most promising strategies to design modified antimicrobial peptides with higher proteolytic stability with the purpose of giving a comprehensive summary of the commonly employed approaches to evaluate and optimize the peptide potentialities.

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“…Amino acid substitution is popular to improve peptide stability against protease digestion, including D - or unnatural amino acids residue substitution [ 121 , 122 ]. For example, Lu et al [ 123 ] synthesized derivatives of the cationic HDP Pep05 (the putative active domain of histatin 5) by substituting L -amino acid residues with D - and unnatural amino acids, such as D -lysine, 4-aminobutanoic acid, and the results showed that both improve the stabilities of the peptides toward proteases.…”

Section: Challenges and Prospectsmentioning

confidence: 99%

The dual antimicrobial and immunomodulatory roles of host defense peptides and their applications in animal production

Wen

et al. 2022

J Animal Sci Biotechnol

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Host defense peptides (HDPs) are small molecules with broad-spectrum antimicrobial activities against infectious bacteria, viruses, and fungi. Increasing evidence suggests that HDPs can also indirectly protect hosts by modulating their immune responses. Due to these dual roles, HDPs have been considered one of the most promising antibiotic substitutes to improve growth performance, intestinal health, and immunity in farm animals. This review describes the antimicrobial and immunomodulatory roles of host defense peptides and their recent applications in animal production.

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Unnatural amino acids: promising implications for the development of new antimicrobial peptides

Cited by 30 publications

References 149 publications

Truncated Pleurocidin Derivative with High Pepsin Hydrolysis Resistance to Combat Multidrug-Resistant Pathogens

Truncated Pleurocidin Derivative with High Pepsin Hydrolysis Resistance to Combat Multidrug-Resistant Pathogens

Lights and Shadows on the Therapeutic Use of Antimicrobial Peptides

The dual antimicrobial and immunomodulatory roles of host defense peptides and their applications in animal production

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