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( Yong Hai Nan ),( Song Yub Shin ) 생화학분자생물학회(구 한국생화학분자생물학회) 2011 BMB Reports Vol.44 No.11
To investigate the effects of disulphide bond position on the salt resistance and lipopolysaccharide (LPS)-neutralizing activity of α-helical homo-dimeric antimicrobial peptides (AMPs), we synthesized an α-helical model peptide (K6L4W1) and its homo-dimeric peptides (di-K6L4W1-N, di-K6L4W1-M, and di-K6L4W1-C) with a disulphide bond at the N-terminus, the central position, and the C-terminus of the molecules, respectively. Unlike K6L4W1 and di-K6L4W1-M, the antimicrobial activity of di-K6L4W1-N and di-K6L4W1-C was unaffected by 150 mM NaCl. Both di-K6L4W1-N and di-K6L4W1-C caused much greater inhibitory effects on nitric oxide (NO) release in LPS-induced mouse macrophage RAW 264.7 cells, compared to di-K6L4W1-M. Taken together, our results indicate that the presence of a disulphide bond at the N- or C-terminus of the molecule, rather than at the central position, is more effective when designing salt-resistant α-helical homo-dimeric AMPs with potent antimicrobial and LPS-neutralizing activities. [BMB reports 2011; 44(11): 747-752]
Design of Pro-rich Model Antimicrobial Peptides with Improved Bacterial Selectivity
Nan, Yong-Hai,Shin, Song-Yub 朝鮮大學校 附設 醫學硏究所 2009 The Medical Journal of Chosun University Vol.33 No.S
To develop novel Pro-rich model antimicrobial peptides with shorter length and higher bacterial selectivity/therapeutic index than a natural Trp/Pro-rich antimicrobial peptide, indolicidin, we synthesized three Pro-rich model antimicrobial peptides composed of Trp, Lys, Leu and Pro resides. Compared to natural indolicidin, the designed Pro-rich model peptides had approximate 6- to 11-fold higher bacterial selectivity/therapeutic index. These designed peptides selectively bind to negatively charged liposomes [L-α-phosphatidylethanolamine (EYPE) / L-α-phosphatidyl-DL-glycerol (EYPG) (7:3, w/w)], mimicking bacterial membranes. This result indicated that the high bacterial selectivity of designed Pro-rich model peptides may due to their selective interaction with negatively charged phospholipids. Taken together, our designed peptides appear to be excellent candidates for future development as a novel antimicrobial agent.
Yong Hai Nan,이봉주,신송엽 대한화학회 2012 Bulletin of the Korean Chemical Society Vol.33 No.9
LL-37 is the only antimicrobial peptide (AMP) of the human cathelicidin family. In addition to potent antimicrobial activity, LL-37 is known to have the potential to inhibit lipolysaccharide (LPS)-induced endotoxic effects. To provide the stability to proteolytic digestion and increase prokaryotic selectivity and/or antiendotoxic activity of two Lys/Trp-substituted 19-meric antimicrobial peptides (a4-W1 and a4-W2) designed from IG-19 (residues 13-31 of LL-37), we synthesized the diastereomeric peptides (a4-W1-D and a4-W2-D) with D-amino acid substitution at positions 3, 7, 10, 13 and 17 of a4-W1 and a4-W2, respectively and the enantiomeric peptides (a4-W1-E and a4-W2-E) composed D-amino acids. The diastereomeric peptides exhibited the best prokaryotic selectivity and effective protease stability, but no or less anti-endotoxic activity. In contrast, the enantiomeric peptides had not only prokaryotic selectivity and anti-endotoxic activity but also protease stability. Our results suggest that the hydrophobicity and α-helicity of the peptide is important for antiendotoxic activity. In particular, the enantiomeric peptides showed potent anti-endotoxic and LPS-neutralizing activities comparable to that of LL-37. Taken together, both a4-W1-E and a4-W2-E holds promise as a template for the development of peptide antibiotics for the treatment of endotoxic shock and sepsis.
Nan, Yong Hai,Park, Ka Hyon,Park, Yoonkyung,Jeon, Young Jin,Kim, Yangmee,Park, Il-Seon,Hahm, Kyung-Soo,Shin, Song Yub Published by Elsevier/North Holland on behalf of t 2009 FEMS microbiology letters Vol.292 No.1
<P>To investigate the effects of positive charge and hydrophobicity on the cell selectivity, mechanism of action and anti-inflammatory activity of a Trp-rich antimicrobial peptide indolicidin (IN), a series of IN analogs with Trp-->Lys substitution were synthesized. All IN analogs displayed an approximately 7- to 18-fold higher cell selectivity, compared with IN. IN, IN-1 and IN-2 depolarized (50-90%) the cytoplasmic membrane potential of Staphylococcus aureus close to minimal inhibitory concentration (5-10 microg mL(-1)). However, other IN analogs (IN-3 and IN-4) displayed very low ability in membrane depolarization even at 40 microg mL(-1). Confocal laser-scanning microscopy revealed that IN-3 and IN-4 penetrated the Escherichia coli cell membrane, whereas IN, IN-1 and IN-2 did not enter the cell membrane. In the gel retardation assay, IN-3 and IN-4 bound more strongly to DNA compared with IN, IN-1 and IN-2. These findings suggest that the mechanism of antimicrobial action of IN-3 and IN-4 may be involved in the inhibition of intracellular functions via interference with DNA/RNA synthesis. Unlike IN, all IN analogs did not inhibit nitric oxide production or inducible nitric oxide synthase mRNA expression in lipopolysaccharide-stimulated mouse macrophage RAW264.7 cells, indicating that the hydrophobicity of IN is more important for anti-inflammatory activity in lipopolysaccharide-treated macrophage cells than the positive charge.</P>
Nan, Yong-Hai,Lee, Bong-Ju,Shin, Song-Yub Korean Chemical Society 2012 Bulletin of the Korean Chemical Society Vol.33 No.9
LL-37 is the only antimicrobial peptide (AMP) of the human cathelicidin family. In addition to potent antimicrobial activity, LL-37 is known to have the potential to inhibit lipolysaccharide (LPS)-induced endotoxic effects. To provide the stability to proteolytic digestion and increase prokaryotic selectivity and/or anti-endotoxic activity of two Lys/Trp-substituted 19-meric antimicrobial peptides (a4-W1 and a4-W2) designed from IG-19 (residues 13-31 of LL-37), we synthesized the diastereomeric peptides (a4-W1-D and a4-W2-D) with D-amino acid substitution at positions 3, 7, 10, 13 and 17 of a4-W1 and a4-W2, respectively and the enantiomeric peptides (a4-W1-E and a4-W2-E) composed D-amino acids. The diastereomeric peptides exhibited the best prokaryotic selectivity and effective protease stability, but no or less anti-endotoxic activity. In contrast, the enantiomeric peptides had not only prokaryotic selectivity and anti-endotoxic activity but also protease stability. Our results suggest that the hydrophobicity and ${\alpha}$-helicity of the peptide is important for anti-endotoxic activity. In particular, the enantiomeric peptides showed potent anti-endotoxic and LPS-neutralizing activities comparable to that of LL-37. Taken together, both a4-W1-E and a4-W2-E holds promise as a template for the development of peptide antibiotics for the treatment of endotoxic shock and sepsis.
Hai-Yan Chen,Yue-Feng Guan,Xue-Yong Huang,Yu-Ting Wu,Fen-Fei Wang,Ju-Fang Gao,Que Zhou,Zhong-Nan Yang,Jia-Yao Liu,Hong-Xia Zhang 한국식물학회 2012 Journal of Plant Biology Vol.55 No.3
We have characterized a new male-sterile mutant in Arabidopsis that exhibits conditional sterility but has restored fertility when drought-stressed. This mutant,multiple impairments in male reproduction 1 (mimr1),shows pleiotropic defects in both vegetative and reproductive development. Examination with dissecting and scanning electron microscopes revealed that its pollen grains are not effectively released from the anther locule after dehiscence, and anther differentiation is defective. Growth of the style and stamen filaments are also abnormal. Histological analysis demonstrated that these phenomena are due not only to a noticeably reduced extension of the stamen but also greater elongation of the pistil. Genetic analysis indicated that mimr1 is a single locus recessive nuclear mutant. The mutation can be mapped to a locus strongly linked to a 1200-kb region on Chromosome 3. Meta-analysis of expression patterning presented several candidate genes in that region. No mutants with similar phenotypes have previously been reported, suggesting that mimr1 is a novel male-sterile locus. Characterization of MIMR1 will provide further insights into the molecular basis for the development of plant reproductive organs.