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Novel Broad-Spectrum Antimicrobial Peptide Derived from Anoplin and Its Activity on Bacterial Pneumonia in Mice
The emergence of multidrug-resistant bacteria has major issues for treating bacterial pneumonia. Currently, anoplin (GLLKRIKTLL-NH2) is a natural antimicrobial candidate derived from wasp venom. In this study, a series of new antimicrobial peptide (AMP) anoplin analogues were designed and synthesize...
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Published in: | Journal of medicinal chemistry 2021-08, Vol.64 (15), p.11247-11266 |
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container_title | Journal of medicinal chemistry |
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creator | Gou, Sanhu Li, Beibei Ouyang, Xu Ba, Zufang Zhong, Chao Zhang, Tianyue Chang, LinLin Zhu, Yuewen Zhang, Jingying Zhu, Ningyi Zhang, Yun Liu, Hui Ni, Jingman |
description | The emergence of multidrug-resistant bacteria has major issues for treating bacterial pneumonia. Currently, anoplin (GLLKRIKTLL-NH2) is a natural antimicrobial candidate derived from wasp venom. In this study, a series of new antimicrobial peptide (AMP) anoplin analogues were designed and synthesized. The relationship between their biological activities and their positive charge, hydrophobicity, amphipathicity, and secondary structure are described. The characteristic shared by these peptides is that positively charged amino acids and hydrophobic amino acids are severally arranged on the hydrophilic and hydrophobic surface of the α-helix to form a completely amphiphilic structure. To achieve ideal AMPs, below the range of the threshold of the cytotoxicity and hemolytic activity, their charges and hydrophobicity were increased as much. Among the new analogues, A-21 (KWWKKWKKWW-NH2) exhibited the greatest antimicrobial activity (geometric mean of minimum inhibitory concentrations = 4.76 μM) against all the tested bacterial strains, high bacterial cell selectivity in vitro, high effectiveness against bacterial pneumonia in mice infected with Klebsiella pneumoniae, and low toxicity in mice (LD50 = 82.01 mg/kg). A-21 exhibited a potent bacterial membrane-damaging mechanism and lipopolysaccharide-binding ability. These data provide evidence that A-21 is a promising antimicrobial candidate for the treatment of bacterial pneumonia. |
doi_str_mv | 10.1021/acs.jmedchem.1c00614 |
format | article |
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Currently, anoplin (GLLKRIKTLL-NH2) is a natural antimicrobial candidate derived from wasp venom. In this study, a series of new antimicrobial peptide (AMP) anoplin analogues were designed and synthesized. The relationship between their biological activities and their positive charge, hydrophobicity, amphipathicity, and secondary structure are described. The characteristic shared by these peptides is that positively charged amino acids and hydrophobic amino acids are severally arranged on the hydrophilic and hydrophobic surface of the α-helix to form a completely amphiphilic structure. To achieve ideal AMPs, below the range of the threshold of the cytotoxicity and hemolytic activity, their charges and hydrophobicity were increased as much. Among the new analogues, A-21 (KWWKKWKKWW-NH2) exhibited the greatest antimicrobial activity (geometric mean of minimum inhibitory concentrations = 4.76 μM) against all the tested bacterial strains, high bacterial cell selectivity in vitro, high effectiveness against bacterial pneumonia in mice infected with Klebsiella pneumoniae, and low toxicity in mice (LD50 = 82.01 mg/kg). A-21 exhibited a potent bacterial membrane-damaging mechanism and lipopolysaccharide-binding ability. 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Med. Chem</addtitle><description>The emergence of multidrug-resistant bacteria has major issues for treating bacterial pneumonia. Currently, anoplin (GLLKRIKTLL-NH2) is a natural antimicrobial candidate derived from wasp venom. In this study, a series of new antimicrobial peptide (AMP) anoplin analogues were designed and synthesized. The relationship between their biological activities and their positive charge, hydrophobicity, amphipathicity, and secondary structure are described. The characteristic shared by these peptides is that positively charged amino acids and hydrophobic amino acids are severally arranged on the hydrophilic and hydrophobic surface of the α-helix to form a completely amphiphilic structure. To achieve ideal AMPs, below the range of the threshold of the cytotoxicity and hemolytic activity, their charges and hydrophobicity were increased as much. Among the new analogues, A-21 (KWWKKWKKWW-NH2) exhibited the greatest antimicrobial activity (geometric mean of minimum inhibitory concentrations = 4.76 μM) against all the tested bacterial strains, high bacterial cell selectivity in vitro, high effectiveness against bacterial pneumonia in mice infected with Klebsiella pneumoniae, and low toxicity in mice (LD50 = 82.01 mg/kg). A-21 exhibited a potent bacterial membrane-damaging mechanism and lipopolysaccharide-binding ability. 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Med. Chem</addtitle><date>2021-08-12</date><risdate>2021</risdate><volume>64</volume><issue>15</issue><spage>11247</spage><epage>11266</epage><pages>11247-11266</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The emergence of multidrug-resistant bacteria has major issues for treating bacterial pneumonia. Currently, anoplin (GLLKRIKTLL-NH2) is a natural antimicrobial candidate derived from wasp venom. In this study, a series of new antimicrobial peptide (AMP) anoplin analogues were designed and synthesized. The relationship between their biological activities and their positive charge, hydrophobicity, amphipathicity, and secondary structure are described. The characteristic shared by these peptides is that positively charged amino acids and hydrophobic amino acids are severally arranged on the hydrophilic and hydrophobic surface of the α-helix to form a completely amphiphilic structure. To achieve ideal AMPs, below the range of the threshold of the cytotoxicity and hemolytic activity, their charges and hydrophobicity were increased as much. Among the new analogues, A-21 (KWWKKWKKWW-NH2) exhibited the greatest antimicrobial activity (geometric mean of minimum inhibitory concentrations = 4.76 μM) against all the tested bacterial strains, high bacterial cell selectivity in vitro, high effectiveness against bacterial pneumonia in mice infected with Klebsiella pneumoniae, and low toxicity in mice (LD50 = 82.01 mg/kg). A-21 exhibited a potent bacterial membrane-damaging mechanism and lipopolysaccharide-binding ability. These data provide evidence that A-21 is a promising antimicrobial candidate for the treatment of bacterial pneumonia.</abstract><pub>American Chemical Society</pub><doi>10.1021/acs.jmedchem.1c00614</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0002-8728-1268</orcidid></addata></record> |
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title | Novel Broad-Spectrum Antimicrobial Peptide Derived from Anoplin and Its Activity on Bacterial Pneumonia in Mice |
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