Incorporation of Non-Canonical Amino Acids into Antimicrobial Peptides: Advances, Challenges, and Perspectives

Du, Yuhui; Li, Li; Zheng, Yue; Liu, Jiaheng; Gong, Julia; Qiu, Zekai; Li, Yanni; Qiao, Jianjun; Huo, Yi-Xin

doi:10.1128/aem.01617-22

Cited by 27 publications

(22 citation statements)

References 182 publications

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“…Therefore, biological approaches that exploit a cell’s protein synthesis machinery to directly produce UAA-containing proteins have been developed. Currently, this is a very active research area, and interested readers are directed to recent reviews (e.g., refs , , and ). Below, we only briefly discuss some of these approaches (Figure ), as well as their applications to incorporate some of the UAAs listed in Table and Table .…”

Section: Methods Of Incorporationmentioning

confidence: 99%

Unnatural Amino Acids for Biological Spectroscopy and Microscopy

Feng,

Wang,

Zhang

et al. 2024

Chem. Rev.

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Due to advances in methods for site-specific incorporation of unnatural amino acids (UAAs) into proteins, a large number of UAAs with tailored chemical and/or physical properties have been developed and used in a wide array of biological applications. In particular, UAAs with specific spectroscopic characteristics can be used as external reporters to produce additional signals, hence increasing the information content obtainable in protein spectroscopic and/or imaging measurements. In this Review, we summarize the progress in the past two decades in the development of such UAAs and their applications in biological spectroscopy and microscopy, with a focus on UAAs that can be used as site-specific vibrational, fluorescence, electron paramagnetic resonance (EPR), or nuclear magnetic resonance (NMR) probes. Wherever applicable, we also discuss future directions.

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Section: Methods Of Incorporationmentioning

confidence: 99%

Unnatural Amino Acids for Biological Spectroscopy and Microscopy

Feng,

Wang,

Zhang

et al. 2024

Chem. Rev.

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“…The efficiency and extent of incorporation of the ncAA is also of concern as there is competition between its canonical counterparts. Optimisation of selective pressure conditions can increase efficiency 233 .…”

Section: Antimicrobial Peptidesmentioning

confidence: 99%

Non‐canonical amino acid bioincorporation into antimicrobial peptides and its challenges

Enninful,

Kuppusamy,

Tiburu

et al. 2024

Journal of Peptide Science

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The rise of antimicrobial resistance and multi‐drug resistant pathogens has necessitated explorations for novel antibiotic agents as the discovery of conventional antibiotics is becoming economically less viable and technically more challenging for biopharma. Antimicrobial peptides (AMPs) have emerged as a promising alternative because of their particular mode of action, broad spectrum and difficulty that microbes have in becoming resistant to them. The AMPs bacitracin, gramicidin, polymyxins and daptomycin are currently used clinically. However, their susceptibility to proteolytic degradation, toxicity profile, and complexities in large‐scale manufacture have hindered their development. To improve their proteolytic stability, methods such as integrating non‐canonical amino acids (ncAAs) into their peptide sequence have been adopted, which also improves their potency and spectrum of action. The benefits of ncAA incorporation have been made possible by solid‐phase peptide synthesis. However, this method is not always suitable for commercial production of AMPs because of poor yield, scale‐up difficulties, and its non‐‘green’ nature. Bioincorporation of ncAA as a method of integration is an emerging field geared towards tackling the challenges of solid‐phase synthesis as a green, cheaper, and scalable alternative for commercialisation of AMPs. This review focusses on the bioincorporation of ncAAs; some challenges associated with the methods are outlined, and notes are given on how to overcome these challenges. The review focusses particularly on addressing two key challenges: AMP cytotoxicity towards microbial cell factories and the uptake of ncAAs that are unfavourable to them. Overcoming these challenges will draw us closer to a greater yield and an environmentally friendly and sustainable approach to make AMPs more druggable.

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“…In contrast, a +2 to +4 positive charge on the peptide has been shown to be optimal for maximal antibacterial activity. 38 On the other hand, D-amino acids 39,40 are known to improve the proteolytic resistance, conformational stability, and overall activity of the AMPs. AMPs usually contain Lys and Arg and are typically susceptible to trypsin proteolysis, which specifically cleaves peptide bonds at the C-terminal end of Lys and Arg.…”

Section: Engineering a Short Peptide As A Potential Ampmentioning

confidence: 99%

A rationally engineered small antimicrobial peptide with potent antibacterial activity

Behera,

Ghosh,

Gupta

et al. 2023

J of Cellular Biochemistry

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Antimicrobial resistance (AMR) is a silent pandemic declared by the WHO that requires urgent attention in the post‐COVID world. AMR is a critical public health concern worldwide, potentially affecting people at different stages of life, including the veterinary and agriculture industries. Notably, very few new‐age antimicrobial agents are in the current developmental pipeline. Thus, the design, discovery, and development of new antimicrobial agents are required to address the menace of AMR. Antimicrobial peptides (AMPs) are an important class of antimicrobial agents for combating AMR due to their broad‐spectrum activity and ability to evade AMR through a multimodal mechanism of action. However, molecular size, aggregability, proteolytic degradation, cytotoxicity, and hemolysis activity significantly limit the clinical application of natural AMPs. The de novo design and engineering of a short synthetic amphipathic AMP (≤16 aa, Mol. Wt. ≤ 2 kDa) with an unusual architecture comprised of coded and noncoded amino acids (NCAAs) is presented here, which demonstrates potent antibacterial activity against a few selected bacterial strains mentioned in the WHO priority list. The designer AMP is conformationally ordered in solution and effectively permeabilizes the outer and inner membranes, leading to bacterial growth inhibition and death. Additionally, the peptide is resistant to proteolysis and has negligible cytotoxicity and hemolysis activity up to 150 μM toward cultured human cell lines and erythrocytes. The designer AMP is unique and appears to be a potent therapeutic candidate, which can be subsequently subjected to preclinical studies to explicitly understand and address the menace of AMR.

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Incorporation of Non-Canonical Amino Acids into Antimicrobial Peptides: Advances, Challenges, and Perspectives

Cited by 27 publications

References 182 publications

Unnatural Amino Acids for Biological Spectroscopy and Microscopy

Unnatural Amino Acids for Biological Spectroscopy and Microscopy

Non‐canonical amino acid bioincorporation into antimicrobial peptides and its challenges

A rationally engineered small antimicrobial peptide with potent antibacterial activity

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