Research output: Contribution to journal › Article › peer-review
Redesigning Arenicin-1, an Antimicrobial Peptide from the Marine Polychaeta Arenicola marina, by Strand Rearrangement or Branching, Substitution of Specific Residues, and Backbone Linearization or Cyclization. / Orlov, Dmitriy S.; Shamova, Olga V.; Eliseev, Igor E.; Zharkova, Maria S.; Chakchir, Oleg B.; Antcheva, Nikolinka; Zachariev, Sotir; Panteleev, Pavel V.; Kokryakov, Vladimir N.; Ovchinnikova, Tatiana V.; Tossi, Alessandro.
In: Marine Drugs, Vol. 17, No. 6, 376, 01.01.2019.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Redesigning Arenicin-1, an Antimicrobial Peptide from the Marine Polychaeta Arenicola marina, by Strand Rearrangement or Branching, Substitution of Specific Residues, and Backbone Linearization or Cyclization
AU - Orlov, Dmitriy S.
AU - Shamova, Olga V.
AU - Eliseev, Igor E.
AU - Zharkova, Maria S.
AU - Chakchir, Oleg B.
AU - Antcheva, Nikolinka
AU - Zachariev, Sotir
AU - Panteleev, Pavel V.
AU - Kokryakov, Vladimir N.
AU - Ovchinnikova, Tatiana V.
AU - Tossi, Alessandro
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Arenicin-1, a β-sheet antimicrobial peptide isolated from the marine polychaeta Arenicola marina coelomocytes, has a potent, broad-spectrum microbicidal activity and also shows significant toxicity towards mammalian cells. Several variants were rationally designed to elucidate the role of structural features such as cyclization, a certain symmetry of the residue arrangement, or the presence of specific residues in the sequence, in its membranolytic activity and the consequent effect on microbicidal efficacy and toxicity. The effect of variations on the structure was probed using molecular dynamics simulations, which indicated a significant stability of the β-hairpin scaffold and showed that modifying residue symmetry and β-strand arrangement affected both the twist and the kink present in the native structure. In vitro assays against a panel of Gram-negative and Gram-positive bacteria, including drug-resistant clinical isolates, showed that inversion of the residue arrangement improved the activity against Gram-negative strains but decreased it towards Gram-positive ones. Variants with increased symmetry were somewhat less active, whereas both backbone-cyclized and linear versions of the peptides, as well as variants with R→K and W→F replacement, showed antimicrobial activity comparable with that of the native peptide. All these variants permeabilized both the outer and the inner membranes of Escherichia coli, suggesting that a membranolytic mechanism of action was maintained. Our results indicate that the arenicin scaffold can support a considerable degree of variation while maintaining useful biological properties and can thus serve as a template for the elaboration of novel anti-infective agents.
AB - Arenicin-1, a β-sheet antimicrobial peptide isolated from the marine polychaeta Arenicola marina coelomocytes, has a potent, broad-spectrum microbicidal activity and also shows significant toxicity towards mammalian cells. Several variants were rationally designed to elucidate the role of structural features such as cyclization, a certain symmetry of the residue arrangement, or the presence of specific residues in the sequence, in its membranolytic activity and the consequent effect on microbicidal efficacy and toxicity. The effect of variations on the structure was probed using molecular dynamics simulations, which indicated a significant stability of the β-hairpin scaffold and showed that modifying residue symmetry and β-strand arrangement affected both the twist and the kink present in the native structure. In vitro assays against a panel of Gram-negative and Gram-positive bacteria, including drug-resistant clinical isolates, showed that inversion of the residue arrangement improved the activity against Gram-negative strains but decreased it towards Gram-positive ones. Variants with increased symmetry were somewhat less active, whereas both backbone-cyclized and linear versions of the peptides, as well as variants with R→K and W→F replacement, showed antimicrobial activity comparable with that of the native peptide. All these variants permeabilized both the outer and the inner membranes of Escherichia coli, suggesting that a membranolytic mechanism of action was maintained. Our results indicate that the arenicin scaffold can support a considerable degree of variation while maintaining useful biological properties and can thus serve as a template for the elaboration of novel anti-infective agents.
KW - Antibacterial
KW - Arenicin-1
KW - Chemical synthesis
KW - Cytotoxic
KW - Marine peptides
KW - Molecular dynamics
KW - Molecular symmetry
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=85068482068&partnerID=8YFLogxK
U2 - 10.3390/md17060376
DO - 10.3390/md17060376
M3 - Article
C2 - 31234579
AN - SCOPUS:85068482068
VL - 17
JO - Marine Drugs
JF - Marine Drugs
SN - 1660-3397
IS - 6
M1 - 376
ER -
ID: 53114898