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1.
Eur J Med Chem ; 186: 111901, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771826

RESUMO

Development of novel antimicrobial agents combating drug resistance is in an urgent need. Herein we report the design and synthesis of a series of short lipo-α/sulfono-γ-AA hybrid peptides. Several short peptides exhibit potent and broad-spectrum antimicrobial activity toward both Gram-positive and Gram-negative bacteria. Membrane depolarization and fluorescence microscopy studies indicate that these short lipo-α/sulfono-γ-AA hybrid peptides can mimic the mechanisms of HDPs to kill bacteria by disrupting bacterial membranes. In addition, these short peptides also show capability to eradicate the biofilm formation of E. coli even at very low concentration. The further development of lipidated α/sulofono-γ-AA hybrid peptides may lead to a new class of antibiotic agents to combat drug resistance.


Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Peptídeos/farmacologia , Peptidomiméticos/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Peptidomiméticos/síntese química , Peptidomiméticos/química , Relação Estrutura-Atividade
2.
Acta Crystallogr D Struct Biol ; 75(Pt 10): 904-917, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588922

RESUMO

Retroviral proteases (RPs) are of high interest owing to their crucial role in the maturation process of retroviral particles. RPs are obligatory homodimers, with a pepsin-like active site built around two aspartates (in DTG triads) that activate a water molecule, as the nucleophile, under two flap loops. Mason-Pfizer monkey virus (M-PMV) is unique among retroviruses as its protease is also stable in the monomeric form, as confirmed by an existing crystal structure of a 13 kDa variant of the protein (M-PMV PR) and its previous biochemical characterization. In the present work, two mutants of M-PMV PR, D26N and C7A/D26N/C106A, were crystallized in complex with a peptidomimetic inhibitor and one mutant (D26N) was crystallized without the inhibitor. The crystal structures were solved at resolutions of 1.6, 1.9 and 2.0 Å, respectively. At variance with the previous study, all of the new structures have the canonical dimeric form of retroviral proteases. The protomers within a dimer differ mainly in the flap-loop region, with the most extreme case observed in the apo structure, in which one flap loop is well defined while the other flap loop is not defined by electron density. The presence of the inhibitor molecules in the complex structures was assessed using polder maps, but some details of their conformations remain ambiguous. In all of the presented structures the active site contains a water molecule buried deeply between the Asn26-Thr27-Gly28 triads of the protomers. Such a water molecule is completely unique not only in retropepsins but also in aspartic proteases in general. The C7A and C106A mutations do not influence the conformation of the protein. The Cys106 residue is properly placed at the homodimer interface area for a disulfide cross-link, but the reducing conditions of the crystallization experiment prevented S-S bond formation. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:Acta_Cryst_D:S2059798319011355.


Assuntos
Endopeptidases/química , Vírus dos Macacos de Mason-Pfizer/enzimologia , Multimerização Proteica , Estrutura Quaternária de Proteína , Endopeptidases/genética , Mutação , Peptidomiméticos/química , Inibidores de Proteases/química
3.
Molecules ; 24(18)2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31546908

RESUMO

Lipid nanoparticles (LNP) are the most potent carriers for the delivery of nucleic acid-based therapeutics. The first FDA approved a short interfering RNA (siRNA) drug that uses a cationic LNP system for the delivery of siRNA against human transthyretin (hTTR). However, preparation of such LNP involves tedious multi-step synthesis with relatively low yields. In the present study, we synthesized cationic peptidomimetic functionalized cholesterol (denote Chorn) in straightforward chemical approaches with high yield. When formulated with helper lipids, Chorn LNPs complexed with siRNA to form nanoparticles with an average diameter of 150 nm to 200 nm. Chorn LNP mediated transfection of a green fluorescence protein (GFP) expressing plasmid resulted in 60% GFP positive cells. Moreover, Chorn LNP delivered siRNA against polo-like kinase 1 (Plk1), a disease related gene in cancer cells and efficiently suppressed the expression of the gene, resulting in significant morphological changes in the cell nuclei. Our data suggested that cholesterol based cationic LNP, prepared through a robust chemical strategy, may provide a promising siRNA delivery system.


Assuntos
Colesterol/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Ácidos Nucleicos/uso terapêutico , Peptidomiméticos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cátions , Proteínas de Ciclo Celular/metabolismo , Colesterol/síntese química , Endocitose , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Fenótipo , Plasmídeos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , RNA Interferente Pequeno/metabolismo
4.
Biochim Biophys Acta Biomembr ; 1861(8): 1502-1509, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31229588

RESUMO

Proteinase 3 (PR3), together with other serine proteases, such as neutrophil elastase (NE) and cathepsin G (CG), regulates inflammatory and immune responses. However, in comparison with NE and CG, there is increasing evidence that PR3 functions significantly differ. In particular, PR3 can bind to cell membranes and such membrane-bound PR3 (mbPR3) might be differently involved in the activation of cytokines, growth factors, cellular receptors, and in the regulation of cell apoptosis. For instance, PR3 membrane binding can block some "eat me" signals, notably, phosphatidylserine membrane lipid, and facilitate non-resolving inflammation. Based on the clear evidence that PR3 membrane binding affects the biological functions of PR3, we designed peptidomimetic inhibitors that can remove mbPR3 from the membrane surface in vitro without influencing PR3 catalytic activity. Such inhibitors, which specifically target PR3 binding to membranes, are still lacking. In particular, we found peptidomimetics that inhibit binding of PR3 to POPC:PS liposomes, which mimic the biological environment of PR3.


Assuntos
Membrana Celular/metabolismo , Mieloblastina/metabolismo , Peptidomiméticos/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Calorimetria/métodos , Membrana Celular/enzimologia , Humanos , Lipossomos , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/metabolismo , Ligação Proteica
5.
Bioconjug Chem ; 30(7): 2011-2022, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31243977

RESUMO

Cell-penetrating peptides (CPPs) have emerged as powerful tools in terms of drug delivery. Those short, often cationic peptides are characterized by their usually low toxicity and their ability to transport diverse cargos inside almost any kinds of cells. Still, one major drawback is their nonselective uptake making their application in targeted cancer therapies questionable. In this work, we aimed to combine the power of a CPP (sC18) with an integrin-targeting unit (c[DKP-f3-RGD]). The latter is composed of the Arg-Gly-Asp peptide sequence cyclized via a diketopiperazine scaffold and is characterized by its high selectivity toward integrin αvß3. The two parts were linked via copper-catalyzed alkyne-azide click reaction (CuAAC), while the CPP was additionally functionalized with either a fluorescent dye or the anticancer drug daunorubicin. Both functionalities allowed a careful biological evaluation of these novel peptide-conjugates regarding their cellular uptake mechanism, as well as cytotoxicity in αvß3 integrin receptor expressing cells versus cells that do not express αvß3. Our results show that the uptake follows a "kiss-and-run"-like model, in which the conjugates first target and recognize the receptor, but translocate mainly by CPP mediation. Thereby, we observed significantly more pronounced toxic effects in αvß3 expressing U87 cells compared to HT-29 and MCF-7 cells, when the cells were exposed to the substances with only very short contact times (15 min). All in all, we present new concepts for the design of cancer selective peptide-drug conjugates.


Assuntos
Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/química , Dicetopiperazinas/administração & dosagem , Portadores de Fármacos/química , Integrina alfaVbeta3/metabolismo , Oligopeptídeos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/metabolismo , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Oligopeptídeos/metabolismo , Peptidomiméticos/administração & dosagem , Peptidomiméticos/química , Peptidomiméticos/farmacologia
6.
Dokl Biochem Biophys ; 485(1): 123-125, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31201630

RESUMO

Previously, we synthesized a dimeric dipeptide mimetic of the brain-derived neurotrophic factor (BDNF) loop 4, GSB-106, which, similarly to BDNF, activated TrkB, PI3K/AKT, and MAPK/ERK. When administered systemically, it exhibited neuroprotective, antidepressant, and antidiabetic activities and stimulated neurogenesis and synaptogenesis. In this study, we established that GSB-106 also exhibits the analgesic activity, typical for BDNF, which was revealed in rats in hot plate and tail flick tests 0.5-48 h after intraperitoneal injection at doses of 0.1 and 1 mg/kg.


Assuntos
Analgésicos , Fator Neurotrófico Derivado do Encéfalo , Dipeptídeos , Peptidomiméticos , Analgésicos/química , Analgésicos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Humanos , Masculino , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Estrutura Secundária de Proteína , Ratos
7.
Mol Cell ; 75(1): 66-75.e5, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31175012

RESUMO

Liquid granules rich in intrinsically disordered proteins and RNA play key roles in critical cellular functions such as RNA processing and translation. Many details of the mechanism via which this occurs remain to be elucidated. Motivated by the lacuna in the field and by the prospects of developing de novo artificial granules that provide extrinsic control of translation, we report a bottom-up approach to engineer ribonucleoprotein granules composed of a recombinant RNA-binding IDP that exhibits phase behavior in water. We developed a kinetic model to illustrate that these granules inhibit translation through reversible or irreversible sequestration of mRNA. Within monodisperse droplets capable of transcription and translation, we experimentally demonstrate temporal inhibition of translation by using designer IDPs that exhibit tunable phase behavior. This work lays the foundation for developing artificial granules that promise to further our mechanistic understanding of their naturally occurring counterparts.


Assuntos
Células Artificiais/metabolismo , Grânulos Citoplasmáticos/genética , Proteínas Intrinsicamente Desordenadas/genética , Peptidomiméticos/metabolismo , RNA Mensageiro/genética , Ribonucleoproteínas/genética , Sequência de Aminoácidos , Células Artificiais/citologia , Grânulos Citoplasmáticos/química , Grânulos Citoplasmáticos/metabolismo , Elastina/química , Elastina/genética , Elastina/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Modelos Biológicos , Peptidomiméticos/química , Transição de Fase , Plasmídeos/genética , Plasmídeos/metabolismo , Biossíntese de Proteínas , Engenharia de Proteínas/métodos , RNA/genética , RNA/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ribonucleoproteínas/química , Ribonucleoproteínas/metabolismo
8.
PLoS Comput Biol ; 15(6): e1007041, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31158220

RESUMO

Cadherins are homophilic cell-cell adhesion molecules whose aberrant expression has often been shown to correlate with different stages of tumor progression. In this work, we investigate the interaction of two peptidomimetic ligands with the extracellular portion of human E-cadherin using a combination of NMR and computational techniques. Both ligands have been previously developed as mimics of the tetrapeptide sequence Asp1-Trp2-Val3-Ile4 of the cadherin adhesion arm, and have been shown to inhibit E-cadherin-mediated adhesion in epithelial ovarian cancer cells with millimolar potency. To sample a set of possible interactions of these ligands with the E-cadherin extracellular portion, STD-NMR experiments in the presence of two slightly different constructs, the wild type E-cadherin-EC1-EC2 fragment and the truncated E-cadherin-(Val3)-EC1-EC2 fragment, were carried out at three temperatures. Depending on the protein construct, a different binding epitope of the ligand and also a different temperature effect on STD signals were observed, both suggesting an involvement of the Asp1-Trp2 protein sequence among all the possible binding events. To interpret the experimental results at the atomic level and to probe the role of the cadherin adhesion arm in the dynamic interaction with the peptidomimetic ligand, a computational protocol based on docking calculations and molecular dynamics simulations was applied. In agreement with NMR data, the simulations at different temperatures unveil high variability/dynamism in ligand-cadherin binding, thus explaining the differences in ligand binding epitopes. In particular, the modulation of the signals seems to be dependent on the protein flexibility, especially at the level of the adhesive arm, which appears to participate in the interaction with the ligand. Overall, these results will help the design of novel cadherin inhibitors that might prevent the swap dimer formation by targeting both the Trp2 binding pocket and the adhesive arm residues.


Assuntos
Caderinas , Biologia Computacional/métodos , Espectroscopia de Ressonância Magnética/métodos , Peptidomiméticos , Caderinas/química , Caderinas/metabolismo , Humanos , Ligantes , Simulação de Dinâmica Molecular , Peptidomiméticos/química , Peptidomiméticos/metabolismo , Ligação Proteica
9.
Eur J Med Chem ; 176: 292-309, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112891

RESUMO

Compounds targeting multiple proteins can have synergistic effects and are therefore of interest in medicinal chemistry. At the same time, inhibiting protein-protein interactions (PPI) is increasingly desired in the treatment of disorders or diseases. The development of non-peptidomimetic inhibitors is still a challenge. Herein we investigate macrocyclic scaffolds with one or two embedded carbohydrates (MECs) that present amino acid side chains, or related isosteres, as pharmacophoric groups. Firstly, retroscreening of the previously reported eannaphane-40 (E40, 40), a MEC presenting two pharmacophoric groups, against a set of 55 receptor-subtypes led to a finding of sub-micromolar inhibitory activity for E40 against three serotonergic isoforms (5HT1A/2A/2B) as well as the Na+ channel and the NK-2 receptor. We synthesised MECs with an additional pharmacophoric group compared to E40, with a view to identifying compounds where the selectivity profile was altered among the protein hits from the retroscreening. MECs were produced based on scaffolds with two monosaccharide residues, leading to the incorporation of a third pharmacophoric group. Later, homology models were prepared for four proteins (5HT1A, 5HT2A, NK2 and site-2 of the sodium channel) whose 3D structure is unknown. Inverse docking of the synthesised compounds led to the selection of a new MEC (MEC-B) for protein binding assays. MEC-B was found to have its selectivity profile modulated, in line with docking prediction, compared to E40. MEC-B is dual inhibitor of both 5-HT1A and the sodium channel with improved selectivity for these proteins compared to 5-HT2A/2B/2C, 5-HT transporter and NK2 receptor. Thus, a new multitargeting compound, with an improved selectivity profile was identified, based on a MEC peptidomimetic scaffold.


Assuntos
Glucosídeos/metabolismo , Compostos Macrocíclicos/metabolismo , Peptidomiméticos/metabolismo , Multimerização Proteica/efeitos dos fármacos , Proteínas/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Desenho de Drogas , Escherichia coli , Glucosídeos/síntese química , Glucosídeos/química , Humanos , Ligantes , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Peptidomiméticos/síntese química , Peptidomiméticos/química , Ligação Proteica , Receptores da Neurocinina-2/metabolismo , Receptores de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Canais de Sódio/metabolismo
10.
Future Med Chem ; 11(9): 1015-1033, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31141413

RESUMO

The horizon of drug discovery is currently expanding to target and modulate protein-protein interactions (PPIs) in globular proteins and intrinsically disordered proteins that are involved in various diseases. To either interrupt or stabilize PPIs, the 3D structure of target protein-protein (or protein-peptide) complexes can be exploited to rationally design PPI modulators (inhibitors or stabilizers) through structure-based molecular design. In this review, we present an overview of experimental and computational methods that can be used to determine 3D structures of protein-protein complexes. Several approaches including rational and in silico methods that can be applied to design peptides, peptidomimetics and small compounds by utilization of determined 3D protein-protein/peptide complexes are summarized and illustrated.


Assuntos
Desenho de Drogas , Peptídeos/farmacologia , Peptidomiméticos/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas/metabolismo , Animais , Descoberta de Drogas/métodos , Humanos , Simulação de Acoplamento Molecular , Peptídeos/química , Peptidomiméticos/química , Ligação Proteica , Proteínas/química
11.
Org Biomol Chem ; 17(16): 3996-4004, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30945720

RESUMO

Phosphoprotein-binding domains interact with cognate phosphorylated targets ruling several biological processes. The impairment of such interactions is often associated with disease development, namely cancer. The breast cancer susceptibility gene 1 (BRCA1) C-terminal (BRCT) domain is involved in the control of complex signaling networks of the DNA damage response. The capture and identification of BRCT-binding proteins and peptides may be used for the development of new diagnostic tools for diseases with abnormal phosphorylation profiles. Here we show that designed cyclic ß-hairpin structures can be used as peptidomimetics of the BRCT domain, with high selectivity in binding to a target phosphorylated peptide. The amino acid residues and spatial constraints involved in the interaction between a phosphorylated peptide (GK14-P) and the BRCT domain were identified and crafted onto a 14-mer ß-hairpin template in silico. Several cyclic peptides models were designed and their binding towards the target peptide and other phosphorylated peptides evaluated through virtual screening. Selected cyclic peptides were then synthesized, purified and characterized. The high affinity and selectivity of the lead cyclic peptide towards the target phosphopeptide was confirmed, and the possibility to capture it using affinity chromatography demonstrated. This work paves the way for the development of cyclic ß-hairpin peptidomimetics as a novel class of affinity reagents for the highly selective identification and capture of target molecules.


Assuntos
Peptidomiméticos/química , Fosfoproteínas/química , Proteína BRCA1/química , Sítios de Ligação , Humanos , Modelos Moleculares
12.
Biomater Sci ; 7(5): 2144-2151, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30882803

RESUMO

Microbial infections have always been serious challenges to human health considering that antibiotics almost inevitably induce microbial resistance. Therefore, it is urgent to develop a new antibacterial agent that is active against drug-resistant bacteria and is less susceptible to microbial resistance. In this work, a series of host defense peptide (HDP) mimicking antibacterial poly-ß-peptides were synthesized, characterized and evaluated for their biological activities. The best poly-ß-peptide within this study (20 : 80 Bu : DM) displays potent and broad spectrum antibacterial activity against antibiotic-resistant super bugs and low toxicity toward mammalian cells. Moreover, these poly-ß-peptides are bactericidal and kill bacteria very fast within 5 min. An antimicrobial resistance test demonstrated that bacteria develop no resistance toward the selected poly-ß-peptides even over 1000 generations. Our studies demonstrate that random copolymers of heterochiral poly-ß-peptides, without the need for defined secondary structures, can mimic the antimicrobial HDP. These results imply the potential application of these poly-ß-peptides as new antimicrobial agents to tackle drug resistant antimicrobial infections.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Antibacterianos/toxicidade , Farmacorresistência Bacteriana/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Peptidomiméticos/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
13.
Protein Pept Lett ; 26(6): 423-434, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-30864495

RESUMO

BACKGROUND: Antibacterial peptidyl derivative - Cystapep 1, was previously found to be active both against antibiotic-resistant staphylococci and streptococci as well as antibioticsusceptible strains of these species. Therefore, it is a promising lead compound to search for new antimicrobial peptidomimetics. OBJECTIVES: We focused on identifying structural elements that are responsible for the biological activity of Cystapep 1 and its five analogues. We tried to find an answer to the question about the mechanism of action of the tested compounds. Therefore, we have investigated in details the possibility of interacting these compounds with biological membrane mimetics. METHODS: The subject compounds were synthesized in solution, purified and characterized by HPLC and mass spectrometry. Then, the staphylococci susceptibility tests were performed and their cytotoxicity was established. The results of Cystapep 1 and its analogues interactions with model target were examined using the DSC and ITC techniques. At the end the spatial structures of the tested peptidomimetics using NMR technique were obtained. RESULTS: Antimicrobial and cytotoxicity tests show that Cystapep 1 and its peptidomimetic V are good drug candidates. DSC and ITC studies indicate that disruption of membrane is not the only possible mechanism of action of Cystapep 1-like compounds. For Cystapep 1 itself, a multi-step mechanism of interaction with a negatively charged membrane is observed, which indicates other processes occurring alongside the binding process. The conformational analysis indicated the presence of a hydrophobic cluster, composed of certain side chains, only in the structures of active peptidomimetics. This can facilitate the anchoring of the peptidyl derivatives to the bacterial membrane. CONCLUSION: An increase in hydrophobicity of the peptidomimetics improved the antimicrobial activity against S. aureus, however there is no simple correlation between the biological activity and the strength of interactions of the peptidyl with bacterial membrane.


Assuntos
Antibacterianos/química , Cistatina C/química , Inibidores de Cisteína Proteinase/química , Dipeptídeos/química , Peptidomiméticos/química , Animais , Antibacterianos/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Modelos Moleculares , Peptidomiméticos/farmacologia , Conformação Proteica , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 168: 386-404, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30831407

RESUMO

Synthetic small molecular antimicrobial peptidomimetics represent a promising new class of potential antibiotics due to their membrane-disrupting ability and their decreased propensity for bacterial resistance. A library of 43 mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics was designed and synthesized based upon previously established lead biarylpeptidomimetics and a known pharmacophore. A reliable, facile and modular synthetic pathway allowed for the efficient synthesis of multiple unique scaffolds which were subjected to divergent derivatization to furnish the amphiphilic compounds. In vitro testing revealed enhanced antibacterial efficacy against a range of pathogenic bacteria, including bacterial isolates with methicillin, vancomycin, daptomycin, or multi-drug resistance. Preliminary time-kill kinetics and membrane-disruption assays revealed a likely membrane-active mechanism for the tested peptidomimetics. An optimal balance between hydrophobicity and cationic charge was found to be essential for reduced cytotoxicity/haemolysis (i.e. membrane selectivity) and enhanced Gram-negative activity. The cationic biaryl amphiphile 81 was identified as a potent, broad-spectrum peptidomimetic with activity against Gram-positive (methicillin-resistant Staphylococcus aureus - MIC = 2 µg/mL) and Gram-negative (Escherichia coli - MIC = 4 µg/mL) pathogenic bacteria.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptidomiméticos/farmacologia , Tensoativos/farmacologia , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Cátions/química , Cátions/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptidomiméticos/química , Relação Estrutura-Atividade , Tensoativos/química , Triazóis/química
15.
Eur J Med Chem ; 170: 203-224, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901686

RESUMO

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 µg/mL against methicillin-resistant Staphylococcus aureus and 8 µg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 µg/mL), Pseudomonas aeruginosa (8 µg/mL) and Klebsiella pneumoniae (16 µg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.


Assuntos
Antibacterianos/química , Antibacterianos/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Clostridium difficile/efeitos dos fármacos , Peptidomiméticos/química , Peptidomiméticos/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Cátions/uso terapêutico , Humanos , Masculino , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Peptidomiméticos/síntese química , Peptidomiméticos/farmacologia , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia , Triazóis/uso terapêutico
16.
Org Biomol Chem ; 17(13): 3433-3445, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30874270

RESUMO

The Ugi-click-strategy was employed for the synthesis of 12-28 membered 1,2,3-triazole derived macrocyclic peptidomimetics. The Ugi reaction with acid components bearing acetylenic fragments and azidoisocyanides provided the corresponding peptidomimetics in up to 97% isolated yield. The subsequent CuAAC click reaction with these bifunctional substrates containing both acetylene and azide groups was investigated to reveal the influence of the structure of Ugi products on the direction of the click-cyclization. It was demonstrated that this approach allows efficient synthesis of either monomeric (12- and 13-membered) or dimeric (24-, 26- and 28-membered) macrocycles prepared in up to 85% yield. The scope and limitations of this method are discussed.


Assuntos
Compostos Macrocíclicos/síntese química , Peptidomiméticos/síntese química , Química Click , Compostos Macrocíclicos/química , Estrutura Molecular , Peptidomiméticos/química
17.
Bioorg Chem ; 85: 534-540, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30807896

RESUMO

A series of d-amino acid-containing peptidomimetics were designed, synthesized as novel polo-like kinase 1 (Plk1) polo-box domain (PBD) inhibitors based on the reported peptide Plk1 PBD inhibitor. Their inhibitory activity to Plk1, Plk2, and Plk3 PBD were evaluated using our fluorescence polarization (FP) assay. Compound 18 bound to Plk1 PBD with IC50 of 0.80 µM and showed nearly no inhibition to Plk2 PBD or Plk3 PBD at 100 µM. Compound 18 induced Hela cells to undergo apoptosis by increasing the ratio of the cells at the G2/M phase by decreasing the neosynthesized proteins in a dose-dependent manner from 50 to 150 µM. Compound 18 showed improved stability in rat plasma compared to l-peptide inhibitor LHSpTA. These novel d-amino acid modified selective Plk1 PBD inhibitors may provide new lead compounds for further optimization.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Peptidomiméticos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/química , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HeLa , Humanos , Peptidomiméticos/síntese química , Peptidomiméticos/química , Domínios Proteicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estabilidade Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Proto-Oncogênicas/química , Ratos , Estereoisomerismo
18.
Biomater Sci ; 7(4): 1281-1285, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30735211

RESUMO

In this communication we report that anchoring αvß3 or α5ß1 integrin-selective RGD peptidomimetics to titanium efficiently tunes mesenchymal stem cell response in vitro and bone growth in rat calvarial defects. Our results demonstrate that this molecular chemistry-derived approach could be successful to engineer instructive coatings for orthopedic applications.


Assuntos
Materiais Biocompatíveis/farmacologia , Osso e Ossos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Oligopeptídeos/farmacologia , Peptidomiméticos/farmacologia , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Regeneração Óssea/efeitos dos fármacos , Integrina alfa5beta1/química , Integrina alfaVbeta3/química , Ligantes , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Peptidomiméticos/química , Ratos , Titânio/química , Titânio/farmacologia , Cicatrização/efeitos dos fármacos
19.
Mol Pharm ; 16(2): 914-920, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30601666

RESUMO

miR-155 plays key promoting roles in several cancers and emerges as an important anticancer therapeutic target. However, the discovery of small molecules that target RNAs is challenging. Peptidomimetics have been shown to be a rich source for discovering novel ligands to regulate cellular proteins. However, the potential of using peptidomimetics for RNA targeting is relatively unexplored. To this end, we designed and synthesized members of a novel 320 000 compound macrocyclic peptidomimetic library. An affinity-based screening protocol led to the identification of a pre-miR-155 binder that inhibits oncogenic miR-155 maturation in vitro and in cell and induces cancer cell apoptosis. The results of this investigation demonstrate that macrocyclic peptidomimetics could serve as a new scaffold for RNA targeting.


Assuntos
MicroRNAs/metabolismo , Peptidomiméticos/metabolismo , Apoptose , Western Blotting , Linhagem Celular , Técnicas de Química Combinatória/métodos , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Células MCF-7 , Peptidomiméticos/química
20.
Molecules ; 24(1)2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30621297

RESUMO

The development of peptidomimetic foldamers that can form well-defined folded structures is highly desirable yet challenging. We previously reported on α-ABpeptoids, oligomers of N-alkylated ß²-homoalanines and found that due to the presence of chiral methyl groups at α-positions, α-ABpeptoids were shown to adopt folding conformations. Here, we report ß-ABpeptoids having chiral methyl group at ß-positions rather than α-positions as a different class of peptoids with backbone chirality. We developed a facile solid-phase synthetic route that enables the synthesis of ß-ABpeptoid oligomers ranging from 2-mer to 8-mer in excellent yields. These oligomers were shown to adopt ordered folding conformations based on circular dichroism (CD) and NMR studies. Overall, these results suggest that ß-ABpeptoids represent a novel class of peptidomimetic foldamers that will find a wide range of applications in biomedical and material sciences.


Assuntos
Aminobutiratos/química , Peptidomiméticos/síntese química , Peptoides/síntese química , Técnicas de Síntese em Fase Sólida , Dicroísmo Circular , Cristalografia por Raios X , Peptidomiméticos/química , Peptoides/química , Conformação Proteica , Dobramento de Proteína , Estereoisomerismo
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