RESUMO
Visceral leishmaniasis (VL) is among the most neglected tropical diseases in the world. Drug cell permeability is essential for killing the intracellular residing parasites responsible for VL, making cell-permeating peptides a logical choice to address VL. Unfortunately, the limited biological stability of peptides restricts their usage. Sequence-specific oligo-N-substituted glycines ('peptoids') are a class of peptide mimics that offers an excellent alternative to peptides in terms of ease of synthesis and good biostability. We tested peptoids against the parasite Leishmania donovani in both forms, that is, intracellular amastigotes and promastigotes. N-alkyl hydrophobic chain addition (lipidation) and bromination of oligopeptoids yielded compounds with good antileishmanial activity against both forms, showing the promise of these antiparasitic peptoids as potential drug candidates to treat VL.
Assuntos
Leishmania donovani , Leishmaniose Visceral , Peptoides , Humanos , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Peptoides/farmacologia , Peptoides/uso terapêutico , Biomimética , PeptídeosRESUMO
Neurodegenerative diseases have emerged as one of the major age-associated diseases in recent years. Hence, the urge to understand the mechanism and to find targeted therapeutics becomes inevitable. Peptide-based compounds have emerged as one of the important tools for their therapy. However, due to a lack of tolerability, specificity, and proteolytic degradation, they have lost their applicability in the broader sense. Thus, the search for suitable alternatives or peptidomimetics becomes an important criterion for neurotherapeutics. One of the versatile peptidomimetics is N-substituted glycines or peptoids, which retain many properties of peptides but successfully evade the drawbacks of peptides. Peptoids are manifested with greater cellular permeability, less immunogenicity, and their ability to be administered intra-nasally. These properties enhance their potential as neurotherapeutics with respect to their peptide counterparts. Recently, peptoids have been explored for neurotherapeutic applications as aggregation inhibitors, cell signaling pathways modulators, and agents for inhibiting inflammation via multiple mechanisms. Peptoids, due to their versatility and low production cost, are becoming popular among peptidomimetics as potential neurotherapeutic agents. In this review, the diverse applications of peptoids with respect to neurodegenerative disease have been explored.
Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Peptidomiméticos/uso terapêutico , Peptoides/uso terapêutico , Humanos , Resultado do TratamentoRESUMO
Cryptococcus neoformans is a fungal pathogen that causes cryptococcal meningitis in immunocompromised individuals. Existing antifungal treatment plans have high mammalian toxicity and increasing drug resistance, demonstrating the dire need for new, nontoxic therapeutics. Antimicrobial peptoids are one alternative to combat this issue. Our lab has recently identified a tripeptoid, AEC5, with promising efficacy and selectivity against C. neoformans. Here, we report studies into the broad-spectrum efficacy, killing kinetics, mechanism of action, in vivo half-life, and subchronic toxicity of this compound. Most notably, these studies have demonstrated that AEC5 rapidly reduces fungal burden, killing all viable fungi within 3 hours. Additionally, AEC5 has an in vivo half-life of 20+ hours and no observable in vivo toxicity following 28 days of daily injections. This research represents an important step in the characterization of AEC5 as a practical treatment option against C. neoformans infections.
Assuntos
Antifúngicos/química , Peptoides/química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Linhagem Celular , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/patogenicidade , Sinergismo Farmacológico , Flucitosina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Meia-Vida , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/patologia , Testes de Sensibilidade Microbiana , Peptoides/metabolismo , Peptoides/farmacologia , Peptoides/uso terapêutico , Sorbitol/químicaRESUMO
The development of neuroprotective therapies is a sought-after goal. By screening combinatorial chemical libraries using in vitro assays, we identified the small molecule BN201 that promotes the survival of cultured neural cells when subjected to oxidative stress or when deprived of trophic factors. Moreover, BN201 promotes neuronal differentiation, the differentiation of precursor cells to mature oligodendrocytes in vitro, and the myelination of new axons. BN201 modulates several kinases participating in the insulin growth factor 1 pathway including serum-glucocorticoid kinase and midkine, inducing the phosphorylation of NDRG1 and the translocation of the transcription factor Foxo3 to the cytoplasm. In vivo, BN201 prevents axonal and neuronal loss, and it promotes remyelination in models of multiple sclerosis, chemically induced demyelination, and glaucoma. In summary, we provide a new promising strategy to promote neuroaxonal survival and remyelination, potentially preventing disability in brain diseases.
Assuntos
Amidas/uso terapêutico , Axônios/efeitos dos fármacos , Encefalite/tratamento farmacológico , Bainha de Mielina/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Peptoides/uso terapêutico , Pirrolidinonas/uso terapêutico , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Imunofluorescência , Glaucoma/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nervo Óptico/efeitos dos fármacos , Proguanil , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , TriazinasRESUMO
Infections caused by Pseudomonas aeruginosa are associated with high morbidity and mortality, especially in immunocompromised patients. These bacteria frequently grow within a biofilm matrix, rendering therapy with conventional antibiotics inefficient; a fact that emphasizes the need for new treatment strategies. Antimicrobial peptidomimetics constitute potential alternatives to traditional antimicrobial agents. However, their application remains limited due to the lack of efficient delivery to their target site in vivo and the risk of high systemic toxicity. Nanogels composed of cross-linked networks of amphiphilic polymers with a therapeutic drug molecule embedded constitute attractive drug delivery systems, as they have been shown to display unique properties such as biocompatibility and biodegrability, as well as confer improved drug stability and reduced drug-mediated cytotoxicity. Here, we report on the first formulation of biopolymer nanogels incorporating a potent antibacterial peptidomimetic. A lysine-based α-peptide/ß-peptoid hybrid with potent activity against P. aeruginosa was designed and formulated into a nanogel together with octenyl succinic anhydride-modified hyaluronic acid in order to improve its cell selectivity. Twelve nanogel formulations were prepared by using a design of experiments setup in order to identify the parameters yielding the highest drug loading and the smallest particle size. Encapsulation of the peptidomimetic into nanogels significantly decreased the cytotoxicity of the peptidomimetic to eukaryotes. The most promising formulation with high encapsulation efficiency (88%) of the peptidomimetic demonstrated a three-fold reduction in cytotoxicity towards hepatocytes along with improved bacterial killing kinetics.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Portadores de Fármacos/química , Peptidomiméticos/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/fisiologia , Antibacterianos/uso terapêutico , Biopolímeros/química , Composição de Medicamentos/métodos , Géis , Hepatócitos/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Lisina/farmacologia , Lisina/uso terapêutico , Testes de Sensibilidade Microbiana , Nanopartículas/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptidomiméticos/uso terapêutico , Peptoides/farmacologia , Peptoides/uso terapêutico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Anidridos Succínicos/química , Testes de ToxicidadeRESUMO
Alzheimer's disease (AD) is an incurable form of dementia affecting millions of people worldwide and costing billions of dollars in health care-related payments, making the discovery of a cure a top health, societal, and economic priority. Peptide-based drugs and immunotherapies targeting AD-associated beta-amyloid (Aß) aggregation have been extensively explored; however, their therapeutic potential is limited by unfavorable pharmacokinetic (PK) properties. Peptoids (N-substituted glycine oligomers) are a promising class of peptidomimetics with highly tunable secondary structures and enhanced stabilities and membrane permeabilities. In this review, the biological activities, structures, and physicochemical properties for several amyloid-targeting peptoids will be described. In addition, metal-chelating peptoids with the potential to treat AD will be discussed since there are connections between the dysregulation of certain metals and the amyloid pathway.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Quelantes , Sistemas de Liberação de Medicamentos/métodos , Peptoides , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Motivos de Aminoácidos , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Quelantes/química , Quelantes/uso terapêutico , Humanos , Peptoides/uso terapêuticoRESUMO
Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-ß (Aß) peptides at residues 12-28 of Aß and this binding modulates Aß accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Aß interaction with Aß12-28 P reduced Aß and tau-related pathology, leading to cognitive improvements in treated AD mice. Recently, we have designed a small peptoid library derived from the Aß12-28 P sequence to screen for new apoE/Aß binding inhibitors with higher efficacy and safety. Peptoids are better drug candidates than peptides due to their inherently more favorable pharmacokinetic properties. One of the lead peptoid compounds, CPO_Aß17-21 P, diminished the apoE/Aß interaction and attenuated the apoE4 pro-fibrillogenic effects on Aß aggregation in vitro as well as apoE4 potentiation of Aß cytotoxicity. CPO_Aß17-21 P reduced Aß-related pathology coupled with cognitive improvements in an AD APP/PS1 transgenic mouse model. Our study suggests the non-toxic, non-fibrillogenic peptoid CPO_Aß17-21 P has significant promise as a new AD therapeutic agent which targets the Aß related apoE pathway, with improved efficacy and pharmacokinetic properties.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Peptoides/uso terapêutico , Animais , Linhagem Celular Tumoral , Cognição , Feminino , Humanos , Masculino , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Peptoides/química , Peptoides/farmacocinética , Ligação ProteicaRESUMO
Membrane proteins play the central roles in a variety of cellular processes, ranging from nutrient uptake and signalling, to cell-cell communication. Their biological functions are directly related to how they fold and assemble; defects often lead to disease. Protein-protein interactions (PPIs) within the membrane are therefore of great interest as therapeutic targets. Here we review the progress in the application of membrane-insertable peptides for the disruption or stabilization of membrane-based PPIs. We describe the design and preparation of transmembrane peptide mimics; and of several categories of peptidomimetics used for study, including d-enantiomers, non-natural amino acids, peptoids, and ß-peptides. Further aspects of the review describe modifications to membrane-insertable peptides, including lipidation and cyclization via hydrocarbon stapling. These approaches provide a pathway toward the development of metabolically stable, non-toxic, and efficacious peptide modulators of membrane-based PPIs. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
Assuntos
Lipídeos de Membrana/química , Proteínas de Membrana/química , Peptídeos Cíclicos/química , Peptidomiméticos/química , Peptoides/química , Motivos de Aminoácidos , Asma/tratamento farmacológico , Asma/metabolismo , Asma/patologia , Membrana Celular/química , Membrana Celular/metabolismo , Desenho de Fármacos , Humanos , Lipídeos de Membrana/antagonistas & inibidores , Lipídeos de Membrana/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/uso terapêutico , Peptidomiméticos/metabolismo , Peptidomiméticos/uso terapêutico , Peptoides/metabolismo , Peptoides/uso terapêutico , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Dobramento de Proteína , EstereoisomerismoRESUMO
Genetic variations in cancer cells are the underpinning for the development of resistance and failure of the treatment by current anticancer drugs. Thus, an ideal drug must overcome failure of treatment and prevents development of drug resistance. There are a wide variety of emerging, easy to prepare and cost effective group of drugs that are collectively called peptoids or peptidomimetics. These new set of drugs exhibit distinct features including protease resistance, are non-immunogenic, do not hinder functionality and backbone polarity, and can adopt different conformations. These drugs have shown promise as diagnostic and therapeutic tools in a wide variety of diseases. Here, we discuss the recent advancement in the design and synthesis of peptoids and use of these drugs in the diganosis and treatment of a wide number of cancers of the lung, prostate, and breast.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Peptoides/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/química , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Peptoides/química , Neoplasias da Próstata/diagnósticoRESUMO
Rapid emergence of antimicrobial resistant organisms necessitates equally rapid methods for the development of new antimicrobial compounds. Of recent interest have been mimics of antimicrobial peptides known as antimicrobial peptoids, which exhibit similar potency to the former but with improved proteolytic stability. Presented herein is a high-throughput method to screen libraries of antimicrobial peptoids immobilized on beads embedded into solid media. Termed the peptoid library agar diffusion (PLAD) assay, this assay allows for individual chemical manipulation of two identical peptoid strands. One strand can be released to diffuse out from a solid support bead and interact with the microorganism during screening. The other strand can be cleaved after screening from beads showing strong antimicrobial activity and analyzed by mass spectrometry to deconvolute the structure of the peptoid. This method was applied to a small library of peptoids to identify an antimicrobial peptoid with modest efficacy against the ESKAPE pathogens.
Assuntos
Anti-Infecciosos/química , Peptoides/química , Anti-Infecciosos/isolamento & purificação , Ensaios de Triagem em Larga Escala/métodos , Espectrometria de Massas , Microesferas , Biblioteca de Peptídeos , Peptoides/uso terapêuticoRESUMO
Incorporation of unnatural amino acids and peptidomimetic residues into therapeutic peptides is highly efficacious and commonly employed, but generally requires laborious trial-and-error approaches. Previously, we demonstrated that C20 peptide has the potential to be a potential antiviral agent. Herein we report our attempt to improve the biological properties of this peptide by introducing peptidomimetics. Through combined alanine, proline, and sarcosine scans coupled with a competitive fluorescence polarization assay developed for identifying antiviral peptides, we enabled to pinpoint peptoid-tolerant peptide residues within C20 peptide. The synergistic benefits of combining these (and other) commonly employed methods could lead to a easily applicable strategy for designing and refining therapeutically-attractive peptidomimetics.
Assuntos
Peptídeos/química , Peptoides/química , Alanina/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Aminoácidos/química , Peptoides/farmacologia , Peptoides/uso terapêutico , Prolina/química , Sarcosina/químicaRESUMO
Polyglutamine(polyQ)-expanded proteins are potential therapeutic targets for the treatment of polyQ expansion disorders such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). Here, we used an amino-terminal fragment of a mutant Huntingtin protein (Htt-N-82Q) as bait in an unbiased screen of a 60,000 peptoid library. Peptoid HQP09 was selected from the isolated hits and confirmed as a specific ligand of Htt-N-82Q and Atxn3-77Q mutant proteins in biochemical experiments. We identified three critical residues in the HQP09 sequence that are important for its activity and generated a minimal derivative, HQP09_9, which maintains the specific polyQ-binding activity. We demonstrated that HQP09 and HQP09_9 inhibited aggregation of Htt-N-53Q in vitro and exerted Ca(2+)-stabilizing and neuroprotective effects in experiments with primary striatal neuronal cultures derived from HD mice. We further demonstrated that intracerebroventricular delivery of HQP09 to an HD mouse model resulted in reduced accumulation of mutant Huntingtin aggregates and improved motor behavioral outcomes. These results suggest that HQP09 and similar peptoids hold promise as novel therapeutics for developing treatments for HD, SCA3, and other polyglutamine expansion disorders.
Assuntos
Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/química , Peptídeos/metabolismo , Peptoides/química , Peptoides/uso terapêutico , Animais , Células Cultivadas , Proteína Huntingtina , Doença de Machado-Joseph/tratamento farmacológico , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Peptídeos/química , Peptoides/farmacologia , Ligação ProteicaRESUMO
Sepsis is a leading cause of mortality that is most often provoked by endotoxins (i.e. lipopolysaccharides; LPS) released by Gram-negative bacteria into the patient's bloodstream during infection. The therapeutic armory currently available for sepsis treatment is poor. We previously identified an LPS-neutralizing small molecule, PTD7. Here we tested the efficacy of novel PTD7-nanoconjugates in a murine model of sepsis. We found that PTD7-based nanoconjugates treated mice had improved survival that it was correlated with a marked decrease in proinflammatory cytokines in the blood. This proves that nanoconjugate-based endotoxin neutralizers can function as intracorporeal neutralizers of bacterial endotoxins.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Lipopolissacarídeos/antagonistas & inibidores , Nanoestruturas/química , Peptoides/administração & dosagem , Peptoides/uso terapêutico , Sepse/tratamento farmacológico , Animais , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular , Bactérias Gram-Negativas/imunologia , Humanos , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Peptoides/química , Polietilenoglicóis/química , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Peptoids are oligomers of N-substituted glycine units. These molecules are almost perfectly suited for combinatorial approaches to drug discovery because large libraries can be synthesized easily from readily available primary amines. Moreover, major advances in screening methodology have allowed peptoid libraries of hundreds of thousands of compounds to be mined inexpensively and quickly for highly specific protein-binding molecules. These advances and the potential utility of peptoids as pharmacological agents are reviewed.