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Tryptic Stability and Antimicrobial Activity of the Derivatives of Polybia-CP with Fine-Tuning Modification in the Side Chain of Lysine

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Abstract

Antimicrobial peptides (AMPs) were believed to be a class of promising antimicrobials to combat the increasing resistant microbes. However, AMPs could be easily degraded by endogenous proteases, which limited their clinic use. Considering that lysine is the only one cationic amino acid residue in polybia-CP which were related to the cleavage of trypsin like serine protease’s digestion, we introduced lysine’s mimics which kept the key function group side chain –NH2 and only varied the methylene chains in the sequence of polybia-CP to investigate the effect of the introduction of non-proteinogenic amino acids on the activity and stability of antimicrobial peptides. In addition, two analogs in which lysine were substituted by the other two proteinogenic cationic amino acids arginine and histidine also were synthesized to evaluate the effect of fine tuning the function group in lysine on its antimicrobial activity and stability. We found that the introduction of amino acids with shortened side chain length of lysine could enhance the trypsin resistance of the derivatives of polybia-CP, while maintain the same or comparable antimicrobial activity with the parent peptide. In addition, while lysine was substituted by histidine, His-CP demonstrated comparable antimicrobial activity and dramatically improved trypsin resistance. Although the analog exhibited excellent antimicrobial activity while lysine was substituted by Arginine residue (Arg-CP), its enzymatic stability was almost the same as its parent peptide. These results suggest that the fine-tuning of side chain of lysine may offer a promising strategy to improve the tryptic stability and retain the antimicrobial activity of antimicrobial peptide.

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 82073679, 81872723, 81601351), CAMS Innovation Fund for Medical Sciences (CIFMS, No. 2019-12M-5-074), Natural Science Foundation of Gansu Province, China (No. 20JR5RA245)  and the Fundamental Research Funds for the Central Universities (No. lzujbky-2020- kb13).

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  1. Feng**g Jia and **aolei Liang have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Institute of Biochemistry and Molecular Biology, Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou University, 2019RU066, Lanzhou, People’s Republic of China

    Feng**g Jia, Jiayi Wang, Lishi Zhang, **g**g Zhou, Yuhang He, Wen** Yan & Kairong Wang

  2. Key Laboratory for Gynecologic Oncology of Gansu Province, Department of Gynecology, the First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China

    **aolei Liang & Fangfang Zhang

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  1. Feng**g Jia
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Jia, F., Liang, X., Wang, J. et al. Tryptic Stability and Antimicrobial Activity of the Derivatives of Polybia-CP with Fine-Tuning Modification in the Side Chain of Lysine. Int J Pept Res Ther 27, 851–862 (2021). https://doi.org/10.1007/s10989-020-10129-0

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