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      Antimicrobial activity and stability of the d-amino acid substituted derivatives of antimicrobial peptide polybia-MPI

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          Abstract

          Antimicrobial peptide has the potential to be developed as new kind of antimicrobial agents with novel action mechanism. However, the susceptibility to protease is a drawback for potential peptides to be clinical used. d-amino acid substitution can be one way to increase the proteolytic stability of peptides. In the present study, we synthesized the d-lysines substituted analog ( d-lys-MPI) and the d-enantiomer of polybia-MPI (D-MPI) to improve the proteolytic resistance of polybia-MPI. Our results showed that, the stability of its d-amino acid partially substituted analog d-lys-MPI was increased. However, it lost antimicrobial activity at the tested concentration with the loss of α-helix content. As shown in the CD spectra, after substitution, the spectra of D-MPI is symmetrical to MPI, indicated it turned into left hand α-helical conformation. Excitingly, the stability of D-MPI toward the tested protease was improved greatly. Notably, the antimicrobial activity of D-MPI was comparable to its L-counterpart MPI, even improved. In addition, the hemolytic activity of D-MPI was lowered. This also indicated that the action target of antimicrobial peptide polybia-MPI was not chiral specific. So, D-MPI may offer a therapeutic strategy to defend the infection of microbes, considering its stability to protease and relatively lower cytotoxicity to human erythrocytes.

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          Most cited references27

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          Antimicrobial peptides: premises and promises.

          Antimicrobial peptides (AMPs) are an important component of the natural defences of most living organisms against invading pathogens. These are relatively small (< 10kDa), cationic and amphipathic peptides of variable length, sequence and structure. During the past two decades several AMPs have been isolated from a wide variety of animals, both vertebrates and invertebrates, and plants as well as from bacteria and fungi. Most of these peptides are obtained from different sources like macrophages, neutrophils, epithelial cells, haemocytes, fat body, reproductive tract, etc. These peptides exhibit broad-spectrum activity against a wide range of microorganisms including Gram-positive and Gram-negative bacteria, protozoa, yeast, fungi and viruses. A few peptides have also been found to be cytotoxic to sperm and tumour cells. AMPs are classified based on the three dimensional structural studies carried out with the help of NMR. The peptides are broadly classified into five major groups namely (a) peptides that form alpha-helical structures, (b) peptides rich in cysteine residues, (c) peptides that form beta-sheet, (d) peptides rich in regular amino acids namely histatin, arginine and proline and (e) peptides composed of rare and modified amino acids. Most of these peptides are believed to act by disrupting the plasma membrane leading to the lysis of the cell. AMPs have been found to be excellent candidates for developing novel antimicrobial agents and a few of these peptides show antimicrobial activity against pathogens causing sexually transmitted infection (STI), including HIV/HSV. Peptides, namely magainin and nisin have been shown to demonstrate contraceptive properties in vitro and in vivo. A few peptides have already entered clinical trials for the treatment of impetigo, diabetic foot ulcers and gastric helicobacter infections. In this review, we discuss the source, structures and mode of action with special reference to therapeutic considerations of various AMPs.
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            Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids.

            9-Fluorenylmethoxycarbonyl (Fmoc) amino acids were first used for solid phase peptide synthesis a little more than a decade ago. Since that time, Fmoc solid phase peptide synthesis methodology has been greatly enhanced by the introduction of a variety of solid supports, linkages, and side chain protecting groups, as well as by increased understanding of solvation conditions. These advances have led to many impressive syntheses, such as those of biologically active and isotopically labeled peptides and small proteins. The great variety of conditions under which Fmoc solid phase peptide synthesis may be carried out represents a truly "orthogonal" scheme, and thus offers many unique opportunities for bioorganic chemistry.
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              Structure, membrane orientation, mechanism, and function of pexiganan--a highly potent antimicrobial peptide designed from magainin.

              The growing problem of bacterial resistance to conventional antibiotic compounds and the need for new antibiotics have stimulated interest in the development of antimicrobial peptides (AMPs) as human therapeutics. Development of topically applied agents, such as pexiganan (also known as MSI-78, an analog of the naturally occurring magainin2, extracted from the skin of the African frog Xenopus laevis) has been the focus of pharmaceutical development largely because of the relative safety of topical therapy and the uncertainty surrounding the long-term toxicology of any new class of drug administered systemically. The main hurdle that has hindered the development of antimicrobial peptides is that many of the naturally occurring peptides (such as magainin), although active in vitro, are effective in animal models of infection only at very high doses, often close to the toxic doses of the peptide, reflecting an unacceptable margin of safety. Though MSI-78 did not pass the FDA approval, it is still the best-studied AMP to date for therapeutic purposes. Biophysical studies have shown that this peptide is unstructured in solution, forms an antiparallel dimer of amphipathic helices upon binding to the membrane, and disrupts membrane via toroidal-type pore formation. This article covers functional, biophysical, biochemical and structural studies on pexiganan.
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                Author and article information

                Contributors
                zhaoyy2013@lzu.edu.cn
                sallyzhangmin@126.com
                choush14@lzu.edu.cn
                wangjy2015@lzu.edu.cn
                pengjx2015@lzu.edu.cn
                zhaop16@lzu.edu.cn
                zhurr13@lzu.edu.cn
                wanghailinyx@163.com
                ly4139@163.com
                +86 931 8912567 , wangkr@lzu.edu.cn
                +86 931 8912567 , yanwj@lzu.edu.cn
                +86 931 8912567 , wangrui@lzu.edu.cn
                Journal
                AMB Express
                AMB Express
                AMB Express
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2191-0855
                29 November 2016
                29 November 2016
                2016
                : 6
                : 122
                Affiliations
                [1 ]Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, 222 Tian Shui South Road, Lanzhou, 730000 People’s Republic of China
                [2 ]The People’s Hospital in Gansu Province, 204 West Donggang Road, Lanzhou, 730000 People’s Republic of China
                Article
                295
                10.1186/s13568-016-0295-8
                5128008
                27900727
                fc469896-290b-4676-b14c-bbef9f3990b1
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 9 November 2016
                : 22 November 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81573265
                Award ID: 91213302, 81473095
                Award ID: 21272108
                Award ID: 81260387
                Award ID: 81360112
                Award Recipient :
                Funded by: The Fundamental Research Funds for the Central Universities
                Award ID: lzujbky-2015-K11; lzujbky-2016-ct01
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004775, Natural Science Foundation of Gansu Province;
                Award ID: 1208RJZ109
                Award Recipient :
                Funded by: Natural Science Foundation of Gansu Province (CN)
                Award ID: 1606RJZA159
                Award Recipient :
                Funded by: The fundamental Research Funds for the Central University
                Award ID: lzujbky-2015-179
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © The Author(s) 2016

                Biotechnology
                antimicrobial peptide,polybia-mpi,stability,d-amino acid substitution
                Biotechnology
                antimicrobial peptide, polybia-mpi, stability, d-amino acid substitution

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