title: Design and synthesis of peptides from bacterial ParE toxin as inhibitors of topoisomerases.
abstract: Toxin-antitoxin (TA) proteic systems encode a toxin and an antitoxin that regulate the growth and death of bacterial cells under various stress conditions. The ParE protein is a toxin that inhibits DNA gyrase activity and thereby blocks DNA replication. Based on the Escherichia coli ParE structure, a series of linear peptides were designed and synthesized by solid-phase methodology. The ability of the peptides to inhibit the activity of bacterial topoisomerases was investigated. Four peptides (ParELC3, ParELC8, ParELC10 and ParELC12), showed complete inhibition of DNA gyrase supercoiling activity with an IC(100) between 20 and 40 μmol L(-1). In contrast to wild-type ParE, the peptide analogues were able to inhibit the DNA relaxation of topoisomerase IV, another type IIA bacterial topoisomerase, with lower IC(100) values. Interestingly only ParELC12 displayed inhibition of the relaxation activity of human topoisomerase II. Our findings reveal new inhibitors of bacterial topoisomerases and are a good starting point for the development of a new class of antibacterial agents that targets the DNA topoisomerases.
authors: UNESP - Institute of Chemistry, Department of Biochemistry and Technological Chemistry, Caixa Postal 355, 14800-900 Araraquara, São Paulo, Brazil.
authors: Luiz Carlos Bertucci
authors: LC
authors: Barbosa
authors: Saulo Santesso
authors: SS
authors: Garrido
authors: Anderson
authors: A
authors: Garcia
authors: Davi Barbosa
authors: DB
authors: Delfino
authors: Laura do Nascimento
authors: Ldo N
authors: Santos
authors: Reinaldo
authors: R
authors: Marchetto
mesh_terms: D000595:Amino Acid Sequence; D001427:Bacterial Toxins / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D027101:DNA Topoisomerase IV / Q000737:chemistry*; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001427:Bacterial Toxins; D010455:Peptides; D059003:Topoisomerase Inhibitors; D027101:DNA Topoisomerase IV