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 -