RESUMO
Antimicrobial peptides (AMPs) are short cationic peptides with a high affinity for membranes and emerged as a promising therapeutic approach with potential for treating infectious diseases. Chemical stabilization of short peptides proved to be a successful approach for enhancing their bio-physical properties. Herein, we designed and synthesized a panel of conformationally constrained antimicrobial peptides with either α-helical or ß-hairpin conformation using templating strategies. These synthetic short constrained peptides possess different topological distributions of hydrophobic and hydrophilic residues and displayed distinct antimicrobial activity. Notably, the conformationally constrained α-helical peptides displayed a faster internalization into the bacteria cells compared to their ß-hairpin analogues. These synthetic short constrained peptides showed killing effects on a broad spectrum of microorganisms mainly through pore formation and membrane damage which provided a potentially promising skeleton for the next generation of stabilized antimicrobial peptides.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Desenho de Fármacos , Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Bactérias/citologia , Infecções Bacterianas/tratamento farmacológico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Secundária de ProteínaRESUMO
Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.
Assuntos
Peptídeos/química , Conformação Proteica em alfa-Hélice , Safrol/análogos & derivados , Dicroísmo Circular , Modelos Moleculares , Oxirredução , Safrol/químicaRESUMO
Thiol-ene reactions have been used in a variety of applications that mostly involve an inter-molecular pathway. Herein, we report a facile method to construct thioether-tethered cyclic peptides via an intra-molecular thiol-ene reaction. This reaction is efficient, selective, and has good residue compatibility. Short peptides with thioether tethers were constructed and were used to construct longer cyclic peptides. This synthetic method may be useful for constructing bioactive peptides. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
Assuntos
Éteres Cíclicos/química , Peptídeos Cíclicos/síntese química , Compostos de Sulfidrila/química , Sequência de Aminoácidos , Compostos Benzidrílicos/química , Química Click/métodosRESUMO
We report a ß-hairpin dual stabilizing strategy: a d-proline-l-proline (d-Pro-l-Pro) dipeptide as the nucleating turn, and a thioether tether as a side-chain linkage at a precisely designed position to stabilize the ß-hairpin. This method was used to modify the C-terminal ß-hairpin moiety of the plant defensin, pv-defensin, in order to obtain a stabilized peptide with enhanced anti-Candida albicans activity (MIC 84-3.0â µm), high serum stability (50 % remaining after 48â h) and low hemolysis (<10 % at 152â µm). This modified peptide penetrated the C.â albicans cell membrane within 5â min and showed high activity against clinically isolated antibiotic-resistant C.â albicans and Candida glabrata strains.
Assuntos
Antifúngicos/química , Candida albicans/efeitos dos fármacos , Defensinas/química , Prolina/química , Antifúngicos/farmacologia , Candida glabrata/efeitos dos fármacos , Defensinas/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estabilidade Proteica , Estrutura Secundária de Proteína , Relação Estrutura-Atividade , SulfetosRESUMO
Defensins are small cationic cysteine rich peptides, which usually contain 18-45 amino acids and possess amphiphilic properties. The term "defensin" was coined as the sequences of rabbit and human leukin/phagocytin molecules were first reported in 1985. Since then, various defensins were isolated and characterized from insects, plants and vertebrates. Using vertebrate defensins as examples, defensins are categorized into three sub-families based on their different patterns of intramolecular disulfide linkages: α defensins, ß defensins, and θ defensins. During the past decades, continuous attentions were casted on various defensins for their broad activity against bacteria, fungi and viruses. In this review, we focus on the effect of characteristic intramolecular disulfide bonds on the antimicrobial activity of defensins. The disulfide bonds are important for holding the defensins in their three dimensional structures, while also contribute to their antimicrobial activity and chemotactic activity. This review summarizes the effects of disulfide bonds, their synthetic formation pathways and potential pharmaceutical applications.
Assuntos
Anti-Infecciosos/química , Defensinas/química , Dissulfetos/química , Animais , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Defensinas/farmacologia , Fungos/efeitos dos fármacos , Humanos , Modelos Moleculares , Vírus/efeitos dos fármacosRESUMO
Increasing antibiotic resistance in human pathogens necessitates the development of new approaches against infections. Targeting virulence regulation at the transcriptional level represents a promising strategy yet to be explored. A global transcriptional regulator, MgrA in Staphylococcus aureus, was identified previously as a key virulence determinant. We have performed a fluorescence anisotropy (FA)-based high-throughput screen that identified 5, 5-methylenedisalicylic acid (MDSA), which blocks the DNA binding of MgrA. MDSA represses the expression of α-toxin that is up-regulated by MgrA and activates the transcription of protein A, a gene down-regulated by MgrA. MDSA alters bacterial antibiotic susceptibilities via an MgrA-dependent pathway. A mouse model of infection indicated that MDSA could attenuate S. aureus virulence. This work is a rare demonstration of utilizing small molecules to block protein-DNA interaction, thus tuning important biological regulation at the transcriptional level.