Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 768
Filtrar
1.
Methods Enzymol ; 698: 1-26, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38886028

RESUMO

N-alkylated glycine residues are the main constituent of peptoids and peptoid-peptide hybrids that are employed across the biomedical and materials sciences. While the impact of backbone N-alkylation on peptide conformation has been extensively studied, less is known about the effect of N-amination on the secondary structure propensity of glycine. Here, we describe a convenient protocol for the incorporation of N-aminoglycine into host peptides on solid support. Amide-to-hydrazide substitution also affords a nucleophilic handle for further derivatization of the backbone. To demonstrate the utility of late-stage hydrazide modification, we synthesized and evaluated the stability of polyproline II helix and ß-hairpin model systems harboring N-aminoglycine derivatives. The described procedures provide facile entry into peptidomimetic libraries for conformational scanning.


Assuntos
Peptídeos , Peptídeos/química , Glicina/química , Glicina/análogos & derivados , Técnicas de Síntese em Fase Sólida/métodos , Peptoides/química , Peptoides/síntese química , Conformação Proteica , Estrutura Secundária de Proteína , Alquilação
2.
Chembiochem ; 25(13): e202400060, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38715149

RESUMO

While plaques comprised of fibrillar Aß aggregates are hallmarks of Alzheimer's disease, soluble Aß oligomers present higher neurotoxicity. Thus, one therapeutic approach is to prevent the formation of Aß oligomers and reduce their associated harmful effects. We have proposed a peptoid mimic of the Aß hydrophobic KLVFF core as an ideal candidate aggregation inhibitor due to its ability to evade proteolytic degradation via repositioning of the side chain from the α-carbon to the amide nitrogen. This peptoid, JPT1, utilizes chiral sidechains to achieve a helical structure, while C-terminal addition of two phenylalanine residues places aromatic groups on two sides of the helix with spacing designed to facilitate interaction with amyloid ß-sheet structure. We have previously shown that JPT1 modulates Aß fibril formation. Here, we demonstrate that JPT1 also modulates Aß oligomerization, and we explore the role of the charge on the linker between the KLVFF mimic and the extended aromatic residues. Additionally, we demonstrate that peptoid-induced changes in Aß oligomerization correlate with attenuation of oligomer-induced nuclear factor-κB activation in SH-SY5Y human neuroblastoma cells. These findings support the therapeutic potential of peptoids to target early stages of Aß aggregation and impact the associated Aß-induced cellular response.


Assuntos
Peptídeos beta-Amiloides , Peptoides , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/química , Humanos , Linhagem Celular Tumoral , Desenho de Fármacos
3.
Org Lett ; 26(19): 4088-4092, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38709636

RESUMO

Access to 1,2,3-triazolium-grafted peptoid macrocycles was developed by macrocyclization and multivalent postmodification of linear peptoid oligomers carrying an alternance of benzylic and propargyl groups as side chains. X-ray analysis and NMR studies revealed a conformational preference for constrained hairpin-shaped structures leading to the facial amphipathic character of these macrocycles. A preliminary evaluation showed the antimicrobial activities of these new cationic amphipathic architectures.


Assuntos
Antibacterianos , Compostos Macrocíclicos , Testes de Sensibilidade Microbiana , Peptidomiméticos , Triazóis , Triazóis/química , Triazóis/farmacologia , Estrutura Molecular , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Peptidomiméticos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Cristalografia por Raios X , Bactérias/efeitos dos fármacos
4.
Eur J Med Chem ; 272: 116447, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38714044

RESUMO

Histone deacetylase 6 (HDAC6) is an emerging drug target to treat oncological and non-oncological conditions. Since highly selective HDAC6 inhibitors display limited anticancer activity when used as single agent, they usually require combination therapies with other chemotherapeutics. In this work, we synthesized a mini library of analogues of the preferential HDAC6 inhibitor HPOB in only two steps via an Ugi four-component reaction as the key step. Biochemical HDAC inhibition and cell viability assays led to the identification of 1g (highest antileukemic activity) and 2b (highest HDAC6 inhibition) as hit compounds. In subsequent combination screens, both 1g and especially 2b showed synergy with DNA methyltransferase inhibitor decitabine in acute myeloid leukemia (AML). Our findings highlight the potential of combining HDAC6 inhibitors with DNA methyltransferase inhibitors as a strategy to improve AML treatment outcomes.


Assuntos
Antineoplásicos , Decitabina , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Leucemia Mieloide Aguda , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Decitabina/farmacologia , Decitabina/química , Relação Estrutura-Atividade , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Aminopiridinas , Benzamidas
5.
Nat Commun ; 15(1): 3264, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627405

RESUMO

A long-standing challenge in bioinspired materials is to design and synthesize synthetic materials that mimic the sophisticated structures and functions of natural biomaterials, such as helical protein assemblies that are important in biological systems. Herein, we report the formation of a series of nanohelices from a type of well-developed protein-mimetics called peptoids. We demonstrate that nanohelix structures and supramolecular chirality can be well-controlled through the side-chain chemistry. Specifically, the ionic effects on peptoids from varying the polar side-chain groups result in the formation of either single helical fiber or hierarchically stacked helical bundles. We also demonstrate that the supramolecular chirality of assembled peptoid helices can be controlled by modifying assembling peptoids with a single chiral amino acid side chain. Computational simulations and theoretical modeling predict that minimizing exposure of hydrophobic domains within a twisted helical form presents the most thermodynamically favorable packing of these amphiphilic peptoids and suggests a key role for both polar and hydrophobic domains on nanohelix formation. Our findings establish a platform to design and synthesize chiral functional materials using sequence-defined synthetic polymers.


Assuntos
Peptoides , Peptoides/química , Aminoácidos
6.
Int J Mol Sci ; 25(8)2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38674048

RESUMO

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.


Assuntos
Anti-Inflamatórios , Lipopolissacarídeos , Microglia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Linhagem Celular , Peptoides/farmacologia , Peptoides/química , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Peptídeos/farmacologia , Peptídeos/química , Fator de Necrose Tumoral alfa/metabolismo , Quimiocina CXCL2/metabolismo , Citocinas/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Quimiocina CCL3/metabolismo , Quimiocina CCL3/genética , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/química
7.
Bioorg Chem ; 147: 107334, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583251

RESUMO

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 µg mL-1 and 6.2 µg mL-1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 µg mL-1 and 11.2 µg mL-1) and 56 %-58 % at 8x MIC (MIC = 35.2 µg mL-1 and 22.4 µg mL-1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.


Assuntos
Antibacterianos , Biofilmes , Testes de Sensibilidade Microbiana , Peptoides , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Dimerização , Escherichia coli/efeitos dos fármacos , Humanos , Eritrócitos/efeitos dos fármacos
8.
Angew Chem Int Ed Engl ; 63(24): e202403263, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38657031

RESUMO

Hierarchical self-assembly represents a powerful strategy for the fabrication of functional materials across various length scales. However, achieving precise formation of functional hierarchical assemblies remains a significant challenge and requires a profound understanding of molecular assembly interactions. In this study, we present a molecular-level understanding of the hierarchical assembly of sequence-defined peptoids into multidimensional functional materials, including twisted nanotube bundles serving as a highly efficient artificial light harvesting system. By employing synchrotron-based powder X-ray diffraction and analyzing single crystal structures of model compounds, we elucidated the molecular packing and mechanisms underlying the assembly of peptoids into multidimensional nanostructures. Our findings demonstrate that incorporating aromatic functional groups, such as tetraphenyl ethylene (TPE), at the termini of assembling peptoid sequences promotes the formation of twisted bundles of nanotubes and nanosheets, thus enabling the creation of a highly efficient artificial light harvesting system. This research exemplifies the potential of leveraging sequence-defined synthetic polymers to translate microscopic molecular structures into macroscopic assemblies. It holds promise for the development of functional materials with precisely controlled hierarchical structures and designed functions.


Assuntos
Peptoides , Peptoides/química , Peptoides/síntese química , Nanoestruturas/química , Nanotubos/química , Modelos Moleculares , Tamanho da Partícula
9.
Methods Enzymol ; 694: 209-236, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38492952

RESUMO

Understanding the conformational behavior of biopolymers is essential to unlocking knowledge of their biophysical mechanisms and functional roles. Single-molecule force spectroscopy can provide a unique perspective on this by exploiting entropic elasticity to uncover key biopolymer structural parameters. A particularly powerful approach involves the use of magnetic tweezers, which can easily generate lower stretching forces (0.1-20 pN). For forces at the low end of this range, the elastic response of biopolymers is sensitive to excluded volume effects, and they can be described by Pincus blob elasticity model that allow robust extraction of the Flory polymer scaling exponent. Here, we detail protocols for the use of magnetic tweezers for force-extension measurements of intrinsically disordered proteins and peptoids. We also discuss procedures for fitting low-force elastic curves to the predictions of polymer physics models to extract key conformational parameters.


Assuntos
Proteínas Intrinsicamente Desordenadas , Peptoides , Elasticidade , Biopolímeros/química , Fenômenos Magnéticos
10.
Cont Lens Anterior Eye ; 47(2): 102124, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38341309

RESUMO

BACKGROUND: Ocular infections caused by antibiotic-resistant pathogens can result in partial or complete vision loss. The development of pan-resistant microbial strains poses a significant challenge for clinicians as there are limited antimicrobial options available. Synthetic peptoids, which are sequence-specific oligo-N-substituted glycines, offer potential as alternative antimicrobial agents to target multidrug-resistant bacteria. METHODS: The antimicrobial activity of synthesised peptoids against multidrug-resistant (MDR) ocular pathogens was evaluated using the microbroth dilution method. Hemolytic propensity was assessed using mammalian erythrocytes. Peptoids were also incubated with proteolytic enzymes, after which their minimum inhibitory activity against bacteria was re-evaluated. RESULTS: Several alkylated and brominated peptoids showed good inhibitory activity against multidrug-resistant Pseudomonas aeruginosa strains at concentrations of ≤15 µg mL-1 (≤12 µM). Similarly, most brominated compounds inhibited the growth of methicillin-resistant Staphylococcus aureus at 1.9 to 15 µg mL-1 (12 µM). The N-terminally alkylated peptoids caused less toxicity to erythrocytes. The peptoid denoted as TM5 had a high therapeutic index, being non-toxic to either erythrocytes or corneal epithelial cells, even at 15 to 22 times its MIC. Additionally, the peptoids were resistant to protease activity. CONCLUSIONS: Peptoids studied here demonstrated potent activity against various multidrug-resistant ocular pathogens. Their properties make them promising candidates for controlling vision-related morbidity associated with eye infections by antibiotic-resistant strains.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Peptoides , Animais , Humanos , Peptoides/farmacologia , Testes de Sensibilidade Microbiana , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Mamíferos
11.
Biomacromolecules ; 25(3): 1391-1407, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38422548

RESUMO

The design, synthesis, and fabrication of functional nanomaterials with specific properties remain a long-standing goal for many scientific fields. The self-assembly of sequence-defined biomimetic synthetic polymers presents a fundamental strategy to explore the chemical space beyond biological systems to create advanced nanomaterials. Moreover, subsequent chemical modification of existing nanostructures is a unique approach for accessing increasingly complex nanostructures and introducing functionalities. Of these modifications, covalent conjugation chemistries, such as the click reactions, have been the cornerstone for chemists and materials scientists. Herein, we highlight some recent advances that have successfully employed click chemistries for the postmodification of assembled one-dimensional (1D) and two-dimensional (2D) nanostructures to achieve applications in molecular recognition, mineralization, and optoelectronics. Specifically, biomimetic nanomaterials assembled from sequence-defined macromolecules such as peptides and peptoids are described.


Assuntos
Materiais Biomiméticos , Nanoestruturas , Peptoides , Química Click , Biomimética , Nanoestruturas/química , Peptídeos , Peptoides/química
12.
Anal Chim Acta ; 1296: 342335, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38401942

RESUMO

In this study, three small peptoids with different structures, named Sil-peptoids, were developed to improve the separation selectivity of zwitterion-exchange/reversed-phase mixed-mode chromatography stationary phases for multi-component complex drugs. Nonpolar, amphoteric, and alkaline drugs were used as test samples to demonstrate their retention behaviors in reversed-phase, ionic, and mixed-mode interactions. It was observed that different carboxyl anions in the small peptoids of the Sil-peptoids had vast differences in their stereo-selectivity. The stereo-selectivity and the influence of Sil-peptoids on the retention behavior of complex drugs and their interaction mechanism for the drug molecules were effectively evaluated through the combination of chromatographic analysis and molecular modeling. Finally, a mixture of drugs consisting of two polar and six non-polar drugs was used to obtain a separation effect with a resolution >1.5. Two other groups of polar antibiotics were used to verify the separation ability of the Sil-peptoids. The results indicated that the Sil-peptoids could separate multiple substances simultaneously. These novel stationary phases can be applied to the analysis of complex multi-component drugs.


Assuntos
Peptoides , Cromatografia , Ânions
13.
ACS Nano ; 18(4): 3497-3508, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38215492

RESUMO

Two-dimensional (2D) materials have attracted intense interest due to their potential for applications in fields ranging from chemical sensing to catalysis, energy storage, and biomedicine. Recently, peptoids, a class of biomimetic sequence-defined polymers, have been found to self-assemble into 2D crystalline sheets that exhibit unusual properties, such as high chemical stability and the ability to self-repair. The structure of a peptoid is close to that of a peptide except that the side chains are appended to the amide nitrogen rather than the α carbon. In this study, we investigated the effect of peptoid sequence on the mechanism and kinetics of 2D assembly on mica surfaces using in situ AFM and time-resolved X-ray scattering. We explored three distinct peptoid sequences that are amphiphilic in nature with hydrophobic and hydrophilic blocks and are known to self-assemble into 2D sheets. The results show that their assembly on mica starts with deposition of aggregates that spread to establish 2D islands, which then grow by attachment of peptoids, either monomers or unresolvable small oligomers, following well-known laws of crystal step advancement. Extraction of the solubility and kinetic coefficient from the dependence of the growth rate on peptoid concentration reveals striking differences between the sequences. The sequence with the slowest growth rate in bulk and with the highest solubility shows almost no detachment; i.e., once a growth unit attaches to the island edge, there is almost no probability of detaching. Furthermore, a peptoid sequence with a hydrophobic tail conjugated to the final carboxyl residue in the hydrophilic block has enhanced hydrophobic interactions and exhibits rapid assembly both in the bulk and on mica. These assembly outcomes suggest that, while the π-π interactions between adjacent hydrophobic blocks play a major role in peptoid assembly, sequence details, particularly the location of charged groups, as well as interaction with the underlying substrate can significantly alter the thermodynamic stability and assembly kinetics.


Assuntos
Peptoides , Peptoides/química , Peptídeos/química , Silicatos de Alumínio , Amidas/química
14.
Biomacromolecules ; 25(2): 1274-1281, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38240722

RESUMO

We have studied the complexation between cationic antimicrobials and polyanionic microgels to create self-defensive surfaces that responsively resist bacterial colonization. An essential property is the stable sequestration of the loaded (complexed) antimicrobial within the microgel under a physiological ionic strength. Here, we assess the complexation strength between poly(acrylic acid) [PAA] microgels and a series of cationic peptoids that display supramolecular structures ranging from an oligomeric monomer to a tetramer. We follow changes in loaded microgel diameter with increasing [Na+] as a measure of the counterion doping level. Consistent with prior findings on colistin/PAA complexation, we find that a monomeric peptoid is fully released at ionic strengths well below physiological conditions, despite its +5 charge. In contrast, progressively higher degrees of peptoid supramolecular structure display progressively greater resistance to salting out, which we attribute to the greater entropic stability associated with the complexation of multimeric peptoid bundles.


Assuntos
Anti-Infecciosos , Microgéis , Peptoides , Peptoides/química , Resinas Acrílicas/química , Anti-Infecciosos/química , Cátions
15.
Org Lett ; 26(5): 1100-1104, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38295374

RESUMO

The first synthesis of macrocyclic α-ABpeptoids with varying lengths is described. X-ray crystal structures reveal that cyclic trimer displays a chair-like conformation with a cct amide sequence and cyclic tetramer has a saddle-like structure with an uncommon cccc amide arrangement. The creation of a DNA-encoded combinatorial library of macrocyclic α-ABpeptoids is described.


Assuntos
DNA , Peptoides , Amidas/química , Cristalografia por Raios X , DNA/química , Biblioteca Gênica , Compostos Macrocíclicos/química , Conformação Molecular , Peptoides/química
16.
Antiviral Res ; 223: 105821, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38272318

RESUMO

Although antimicrobial peptides have been shown to inactivate viruses through disruption of their viral envelopes, clinical use of such peptides has been hampered by a number of factors, especially their enzymatically unstable structures. To overcome the shortcomings of antimicrobial peptides, peptoids (sequence-specific N-substituted glycine oligomers) mimicking antimicrobial peptides have been developed. We aimed to demonstrate the antiviral effects of antimicrobial peptoids against hepatitis B virus (HBV) in cell culture. The anti-HBV activity of antimicrobial peptoids was screened and evaluated in an infection system involving the HBV reporter virus and HepG2.2.15-derived HBV. By screening with the HBV reporter virus infection system, three (TM1, TM4, and TM19) of 12 peptoids were identified as reducing the infectivity of HBV, though they did not alter the production levels of HBs antigen in cell culture. These peptoids were not cytotoxic at the evaluated concentrations. Among these peptoids, TM19 was confirmed to reduce HBV infection most potently in a HepG2.2.15-derived HBV infection system that closely demonstrates authentic HBV infection. In cell culture, the most effective administration of TM19 was virus treatment at the infection step, but the reduction in HBV infectivity by pre-treatment or post-treatment of cells with TM19 was minimal. The disrupting effect of TM19 targeting infectious viral particles was clarified in iodixanol density gradient analysis. In conclusion, the peptoid TM19 was identified as a potent inhibitor of HBV. This peptoid prevents HBV infection by disrupting viral particles and is a candidate for a new class of anti-HBV reagents.


Assuntos
Anti-Infecciosos , Hepatite B , Peptoides , Humanos , Vírus da Hepatite B , Peptoides/farmacologia , Peptoides/química , Hepatite B/tratamento farmacológico , Técnicas de Cultura de Células , Antivirais/farmacologia , Peptídeos Antimicrobianos
17.
Chemistry ; 30(6): e202303330, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-37948294

RESUMO

Controlling amide bond geometries and the secondary structures of ß-peptoids is a challenging task as they contain several rotatable single bonds in their backbone. Herein, we describe the synthesis and conformational properties of novel "ß-azapeptoids" with confined dihedrals. We discuss how the acylhydrazide sidechains in these molecules enforce trans amide geometries (ω ~180°) via steric and stereoelectronic effects. We also show that the Θ(Cα -Cß ) and Ψ(OC-Cα ) backbone torsions of ß-azapeptoids occupy a narrow range (170-180°) that can be rationalized by the staggered conformational preference of the backbone methylene carbons and a novel backbone nO →σ*Cß-N interaction discovered in this study. However, the ϕ (Cß -N) torsion remains freely rotatable and, depending on ϕ, the sidechains can be parallel, perpendicular, and anti-parallel relative to each other. In fact, we observed parallel and perpendicular relative orientations of sidechains in the crystal geometries of ß-azapeptoid dimers. We show that ϕ of ß-azapeptoids can be controlled by incorporating a bulky substituent at the backbone ß-carbon, which could provide complete control over all the backbone dihedrals. Finally, we show that the ϕ and Ψ dihedrals of ß-azapeptoids resemble that of a PPII helix and they retain PPII structure when incorporated in Host-guest proline peptides.


Assuntos
Peptidomiméticos , Peptoides , Peptídeos/química , Peptoides/química , Amidas/química , Estrutura Secundária de Proteína
18.
Chemistry ; 30(2): e202302937, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-37939246

RESUMO

This study presents an efficient method for on-resin dimer generation through self-condensation of 3,3-dimethoxypropionic acid-modified molecules, resulting in 2-pyridones. The approach demonstrated remarkable versatility by producing homodimers of peptides, peptoids, and non-peptidic ligands. Its ease of application, broad utility, and mild reaction conditions not only hold significance for peptide and peptoid research but also offer potential for the on-resin development of a wide range of bivalent ligands.


Assuntos
Peptoides , Técnicas de Síntese em Fase Sólida , Técnicas de Síntese em Fase Sólida/métodos , Peptídeos/química , Peptoides/química , Piridonas , Ligantes
19.
Bioorg Med Chem ; 97: 117560, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-38103535

RESUMO

Epithelial-to-mesenchymal transition (EMT) endows epithelia-derived cancer cells with properties of stem cells that govern cancer invasion and metastasis. Vimentin is one of the best studied EMT markers and recent reports indicate that vimentin interestingly translocated onto cell surface under various tumor conditions. We recently reported a cell surface vimentin (CSV) specific peptoid antagonist named JM3A. We now investigated the selective antagonist activity of the optimized homo-dimeric version of JM3A, JM3A-L2D on stem-like cancer cells or cancer stem cells (CSCs) over normal cells in non-small cell lung cancer (NSCLC). Homo-dimerization of JM3A provided the avidity effect and improved the biological activity compared to the monomeric version. We first optimized the central linker length of the dimer by designing seven JM3A derivatives with varying linker lengths/types and evaluated the anti-cancer activity using the standard MTS cell viability assay. The most optimized derivative contains a central lysine linker and two glycines, named JM3A-L2D, which displayed 100 nM vimentin binding affinity (Kd) with an anti-cancer activity (IC50) of 6.7 µM on H1299 NSCLC cells. This is a 190-fold improvement in binding over the original JM3A. JM3A-L2D exhibited better potency on high vimentin-expressing NSCLC cells (H1299 and H460) compared to low vimentin-expressing NSCLC cells (H2122). No activity was observed on normal bronchial HBEC3-KT cells. The anti-CSC activity of JM3A-L2D was evaluated using the standard colony formation assay and JM3A-L2D disrupted the colony formation with IC50 âˆ¼ 400 nM. In addition, JM3A-L2D inhibited cell migration activity at IC50 âˆ¼ 2 µM, assessed via wound healing assay. The underlying mechanism of action seems to be the induction of apoptosis by JM3A-L2D on high-vimentin expressing H1229 and H460 NSCLC cells. Our optimized highly CSV selective peptoid has the potential to be developed as an anti-cancer drug candidate, especially considering the high serum stability and economical synthesis of peptoids.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Peptoides , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas , Peptoides/farmacologia , Peptoides/metabolismo , Vimentina/metabolismo
20.
Angew Chem Int Ed Engl ; 63(7): e202318011, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38131886

RESUMO

Antimicrobial peptides (AMPs) exhibit mighty antibacterial properties without inducing drug resistance. Achieving much higher selectivity of AMPs towards bacteria and normal cells has always been a continuous goal to be pursued. Herein, a series of sulfonium-based polypeptides with different degrees of branching and polymerization were synthesized by mimicking the structure of vitamin U. The polypeptide, G2 -PM-1H+ , shows both potent antibacterial activity and the highest selectivity index of 16000 among the reported AMPs or peptoids (e.g., the known index of 9600 for recorded peptoid in "Angew. Chem. Int. Ed., 2020, 59, 6412."), which can be attributed to the high positive charge density of sulfonium and the regulation of hydrophobic chains in the structure. The antibacterial mechanisms of G2 -PM-1H+ are primarily ascribed to the interaction with the membrane, production of reactive oxygen species (ROS), and disfunction of ribosomes. Meanwhile, altering the degree of alkylation leads to selective antibacteria against either gram-positive or gram-negative bacteria in a mixed-bacteria model. Additionally, both in vitro and in vivo experiments demonstrated that G2 -PM-1H+ exhibited superior efficacy against methicillin-resistant Staphylococcus aureus (MRSA) compared to vancomycin. Together, these results show that G2 -PM-1H+ possesses high biocompatibility and is a potential pharmaceutical candidate in combating bacteria significantly threatening human health.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Peptoides , Vitamina U , Humanos , Vitamina U/farmacologia , Peptídeos/química , Antibacterianos/farmacologia , Antibacterianos/química , Vancomicina/farmacologia , Peptoides/química , Bactérias , Peptídeos Antimicrobianos , Testes de Sensibilidade Microbiana
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...