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1.
Vestn Oftalmol ; 136(5): 58-66, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33056965

RESUMO

PURPOSE: To evaluate the influence of prolonged neuroprotective therapy on disease progression in patients with primary open-angle glaucoma (POAG) with compensated intraocular pressure (IOP). MATERIAL AND METHODS: The study included 147 patients with stages I-II POAG (249 eyes) who were randomized into the main (69 patients, 119 eyes) and control groups (78 patients, 130 eyes). Patients of the main group underwent retinalamin treatment course every 6 months. Patients were examined before enrolling and then every 3 months during the 24-months follow-up including optical coherence tomography (OCT; RNFL - retinal nerve fiber layer, NRR - neuroretinal rim, GCL - ganglion cell layer) and static perimetry (MD - mean deviation, PSD - pattern standard deviation). RESULTS: Visual acuity and refraction did not change in either group (p>0.05). IOP increased in the control group (p=0.033). There was no difference between the groups by the 24th month (p=0.87). No MD changes were noted in the main (p=0.45) and control groups (p=0.27). PSD changed in the main (4.84±3.21 and 6.01±2.584 dB in the beginning and the end, respectively, p=0.0004) and the control groups (3.46±2.23 and 5.86±2.26 dB, respectively; p<0.0001). The groups differed in MD and PSD initially (p=0.15; p=0.02) and became equal by the end (p=0.59; p=0.53). RNFL did not change significantly in the main group (p=0.078) and decreased from 83.5±22.47 to 76.7±20.7 µm in the control group (p=0.001); no differences between the groups were noted in the beginning (p=0.276) or in the end of the study (p=0.524). NRR increased in the main group from 222±88.94 to 231±99.3 (p=0.012), and decreased in the control group from 248±87.09 to 234±96.2 (p=0.0006); no differences were found between groups in the beginning or in the end of the study (p=0.109; p=0.909). GCL thickness did not change either in the main, or in the control group (p=0.211; p=0.16), with no difference between the group noted in the beginning or the end of the study (p=0.44; p=0.51). CONCLUSION: Regular treatment with retinalamin arrests the development of glaucomatous optic neuropathy. Longer-term research is required to study its influence on the visual function and the quality of life.


Assuntos
Glaucoma , Peptídeos , Qualidade de Vida , Progressão da Doença , Humanos , Fibras Nervosas , Peptídeos/uso terapêutico , Células Ganglionares da Retina , Tomografia de Coerência Óptica , Acuidade Visual
2.
Molecules ; 25(19)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987757

RESUMO

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Fármacos do Sistema Respiratório/uso terapêutico , Doença Aguda , Anti-Inflamatórios/síntese química , Antivirais/síntese química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Fatores Imunológicos/síntese química , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Peptídeos/síntese química , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/prevenção & controle , Insuficiência Respiratória/virologia , Fármacos do Sistema Respiratório/síntese química , Relação Estrutura-Atividade
3.
PLoS One ; 15(8): e0232302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822373

RESUMO

Sepsis is a life-threatening condition due to a dysregulated immunological response to infection. Apart from source control and broad-spectrum antibiotics, management is based on fluid resuscitation and vasoactive drugs. Fluid resuscitation implicates the risk of volume overload, which in turn is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality. Antisecretory factor (AF), an endogenous protein, is detectable in most tissues and in plasma. The biologically active site of the protein is located in an 8-peptide sequence, contained in a synthetic 16-peptide fragment, named AF-16. The protein as well as the peptide AF-16 has multiple modulatory effects on abnormal fluid transport and edema formation/resolution as well as in a variety of inflammatory conditions. Apart from its' anti-secretory and anti-inflammatory characteristics, AF is an inhibitor of capillary leakage in intestine. It is not known whether the protein AF or the peptide AF-16 can ameliorate symptoms in sepsis. We hypothesized that AF-16 decreases the degree of hemodynamic instability, the need of fluid resuscitation, vasopressor dose and tissue edema in fecal peritonitis. To test the hypothesis, we induced peritonitis and sepsis by injecting autologous fecal solution into abdominal cavity of anesthetized pigs, and randomized (in a blind manner) the animals to intervention (AF-16, n = 8) or control (saline, n = 8) group. After the onset of hemodynamic instability (defined as mean arterial pressure < 60 mmHg maintained for > 5 minutes), intervention with AF-16 (20 mg/kg (50 mg/ml) in 0.9% saline) intravenously (only the vehicle in the control group) and a protocolized resuscitation was started. We recorded respiratory and hemodynamic parameters hourly for twenty hours or until the animal died and collected post mortem tissue samples at the end of the experiment. No differences between the groups were observed regarding hemodynamics, overall fluid balance, lung mechanics, gas exchange or histology. However, liver wet-to-dry ratio remained lower in AF-16 treated animals as compared to controls, 3.1 ± 0.4, (2.7-3.5, 95% CI, n = 8) vs 4.0 ± 0.6 (3.4-4.5, 95% CI, n = 8), p = 0.006, respectively. Bearing in mind the limited sample size, this experimental pilot study suggests that AF-16 may inhibit sepsis induced liver edema in peritonitis-sepsis.


Assuntos
Edema/tratamento farmacológico , Peptídeos/farmacologia , Peritonite/complicações , Sepse/complicações , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Edema/complicações , Edema/patologia , Edema/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hemoglobinas/metabolismo , Interleucina-6/sangue , Lactatos/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Peptídeos/uso terapêutico , Projetos Piloto , Troca Gasosa Pulmonar/efeitos dos fármacos , Suínos , Fator de Necrose Tumoral alfa/sangue , Resistência Vascular/efeitos dos fármacos
4.
Nat Commun ; 11(1): 4252, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843628

RESUMO

The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. Here, we show that a defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alkaline peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.


Assuntos
Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Linhagem Celular , Endossomos/química , Endossomos/efeitos dos fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Vírus da Influenza A/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Ligação Proteica , Conformação Proteica , Rhinovirus/efeitos dos fármacos , Rhinovirus/metabolismo , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
5.
Int J Mol Sci ; 21(15)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32718020

RESUMO

The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Pandemias , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
6.
Future Med Chem ; 12(18): 1647-1656, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32672061

RESUMO

During a disease outbreak/pandemic situation such as COVID-19, researchers are in a prime position to identify and develop peptide-based therapies, which could be more rapidly and cost-effectively advanced into a clinical setting. One drawback of natural peptide drugs, however, is their proteolytic instability; peptidomimetics can help to overcome this caveat. In this review, we summarize peptide and peptide-based therapeutics that target one main entry pathway of SARS-CoV-2, which involves the host ACE2 receptor and viral spike (S) protein interaction. Furthermore, we discuss the advantages of peptidomimetics and other potential targets that have been studied using peptide-based therapeutics for COVID-19.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Peptídeos/uso terapêutico , Peptidomiméticos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Humanos , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Internalização do Vírus
7.
Life Sci ; 256: 117960, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534033

RESUMO

BACKGROUND: Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS: 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS: Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION: Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.


Assuntos
Constipação Intestinal/complicações , Constipação Intestinal/fisiopatologia , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/fisiopatologia , Peptídeos/uso terapêutico , Tadalafila/uso terapêutico , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Colo/fisiopatologia , Constipação Intestinal/tratamento farmacológico , GMP Cíclico/metabolismo , Fezes/química , Trânsito Gastrointestinal/efeitos dos fármacos , Hipocampo/metabolismo , Intestino Grosso/metabolismo , Masculino , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Reflexo/efeitos dos fármacos , Natação , Tadalafila/farmacologia , Água
8.
Adv Gerontol ; 33(2): 299-306, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593244

RESUMO

Neurodegenerative diseases are a heterogeneous group of nervous system pathologies. They are found mainly in people of an older age group. The incidence of neurodegenerative diseases is continuously growing due to an increase in the average life expectancy of the population. At the moment, there are no effective and safe treatments for neurodegenerative diseases, which are most often diagnosed at the stage of decompensation, when therapy is ineffective and does not bring positive outcomes. Most of the currently used drugs act only symptomatically. The review provides analyzed data and information about the prospects of using peptide bioregulators as neuroprotectors with high physiological activity and low immunogenicity.


Assuntos
Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Idoso , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos/uso terapêutico
9.
Am J Kidney Dis ; 76(3): 321-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32475604

RESUMO

RATIONALE & OBJECTIVE: Comparative benefits and harms of calcimimetic agents used for the treatment of secondary hyperparathyroidism have not been well characterized. We sought to compare the effectiveness of 3 calcimimetic agents using published data. STUDY DESIGN: Systematic review of randomized controlled trials and network meta-analysis. SETTING & STUDY POPULATION: Adults with chronic kidney disease enrolled in a clinical trial of a calcimetic agent. SEARCH STRATEGY & SOURCES: MEDLINE, EMBASE, CENTRAL (from February 7, 2013, to November 21, 2019), and a published meta-analysis. DATA EXTRACTION: Two reviewers independently extracted the study data, assessed risk of bias, and rated evidence certainty using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. ANALYTICAL APPROACH: Frequentist network meta-analysis was conducted. The primary review outcomes were achievement of a target reduction in serum parathyroid hormone (PTH) levels and hypocalcemia. Additional outcomes were nausea, vomiting, serious adverse events, all-cause mortality, cardiovascular mortality, heart failure, and fracture. RESULTS: 36 trials (11,247 participants) were included. All except 4 trials involved dialysis patients. Median follow-up was 26 weeks (range, 1 week to 21.2 months). Compared with placebo, calcimimetic agents had higher odds of achieving target PTH levels with high or moderate certainty. Etelcalcetide had the highest odds of achieving a PTH target compared with evocalcet (OR, 4.93; 95% CI, 1.33-18.2) and cinacalcet (OR, 2.78; 95% CI, 1.19-6.67). Etelcalcetide appeared to cause more hypocalcemia than cinacalcet and evocalcet. Cinacalcet and to a lesser extent etelcalcetide appeared to cause more nausea than placebo. Differences in risk for mortality, cardiovascular end points, or fractures across calcimimetic agents could not be discerned with sufficient certainty. LIMITATIONS: Lack of longer-term data; heterogeneous end point definitions. CONCLUSIONS: Evidence of the benefits of calcimimetic therapy is limited to short-term assessment of a putative surrogate outcome (serum PTH). Although etelcalcetide was associated with the largest reduction in PTH levels, side-effect profiles differed across the 3 calcimimetic agents, making it not possible to identify 1 preferred agent.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Naftalenos/uso terapêutico , Peptídeos/uso terapêutico , Pirrolidinas/uso terapêutico , Adulto , Calcimiméticos/efeitos adversos , Cálcio/sangue , Doenças Cardiovasculares/epidemiologia , Cinacalcete/efeitos adversos , Comorbidade , Feminino , Fraturas Ósseas/epidemiologia , Insuficiência Cardíaca/epidemiologia , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Masculino , Mortalidade , Naftalenos/efeitos adversos , Náusea/induzido quimicamente , Hormônio Paratireóideo/sangue , Peptídeos/efeitos adversos , Pirrolidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Resultado do Tratamento , Vômito/induzido quimicamente
10.
Nat Rev Drug Discov ; 19(6): 389-413, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494050

RESUMO

Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) - nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first-in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties.


Assuntos
Desenho de Fármacos , Peptídeos , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Terapia de Alvo Molecular , Biblioteca de Peptídeos , Peptídeos/farmacocinética , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Ligação Proteica , Transdução de Sinais
11.
Peptides ; 130: 170328, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32380200

RESUMO

An outbreak caused by 2019 novel coronavirus (2019-nCoV) was first identified in Wuhan City, Hubei Province, China. The new virus was later named SARS-CoV-2. The virus has affected tens of thousands of patients in the world. The infection of SARS-CoV-2 causes severe pneumonia and even death. It is urgently needed to find a therapeutic method to treat patients with SARS-CoV-2 infection. Studies showed that the surface spike (S) protein is essential for the coronavirus binding and entry of host cells. The heptad repeats 1 and 2 (HR1 and HR2) in the S protein play a decisive role in the fusion of the viral membrane with the host cell membrane. We predicted the HR1 and HR2 regions in S protein by sequence alignment. We simulated a computational model of HR1/2 regions and the fusion core. The binding energy of HR1 and HR2 of the fusion core was -33.4 kcal/mol. We then designed antivirus peptides by molecular dynamics simulation of the fusion core. The binding energy of HR2-based antiviral peptide to HR1 was -43.0 kcal/mol, which was stronger than the natural stage of the fusion core, suggesting that the predicted antiviral peptide can competitively bind with HR1 to prevent forming of the fusion core. The antiviral peptides can prevent SARS-CoV-2 membrane fusion and can potentially be used for the prevention and treatment of infections.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Sequência de Aminoácidos , Antivirais/uso terapêutico , Simulação por Computador , Humanos , Fusão de Membrana , Simulação de Dinâmica Molecular , Pandemias , Estrutura Secundária de Proteína , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas do Envelope Viral/antagonistas & inibidores , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
12.
Nat Biomed Eng ; 4(5): 560-571, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32393891

RESUMO

The oral administration of peptide drugs is hampered by their metabolic instability and limited intestinal uptake. Here, we describe a method for the generation of small target-specific peptides (less than 1,600 Da in size) that resist gastrointestinal proteases. By using phage display to screen large libraries of genetically encoded double-bridged peptides on protease-resistant fd bacteriophages, we generated a peptide inhibitor of the coagulation Factor XIa with nanomolar affinity that resisted gastrointestinal proteases in all regions of the gastrointestinal tract of mice after oral administration, enabling more than 30% of the peptide to remain intact, and small quantities of it to reach the blood circulation. We also developed a gastrointestinal-protease-resistant peptide antagonist for the interleukin-23 receptor, which has a role in the pathogenesis of Crohn's disease and ulcerative colitis. The de novo generation of targeted peptides that resist proteolytic degradation in the gastrointestinal tract should help the development of effective peptides for oral delivery.


Assuntos
Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Proteólise , Administração Oral , Sequência de Aminoácidos , Animais , Técnicas de Visualização da Superfície Celular , Cristalografia por Raios X , Feminino , Trato Gastrointestinal/metabolismo , Humanos , Isomerismo , Camundongos Endogâmicos BALB C , Modelos Moleculares , Peptídeo Hidrolases/metabolismo , Biblioteca de Peptídeos , Peptídeos/química , Estabilidade Proteica , Estrutura Secundária de Proteína , Receptores de Interleucina/antagonistas & inibidores , Receptores de Interleucina/metabolismo
13.
ACS Nano ; 14(4): 5143-5147, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: covidwho-52399

RESUMO

Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.


Assuntos
Betacoronavirus/efeitos dos fármacos , Química Computacional , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Simulação de Dinâmica Molecular , Peptídeos , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Humanos , Pandemias , Peptídeos/química , Peptídeos/uso terapêutico , Peptidil Dipeptidase A/efeitos dos fármacos , Conformação Proteica , Conformação Proteica em alfa-Hélice
14.
Physiol Genomics ; 52(5): 217-221, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: covidwho-47305
15.
Diabetes Res Clin Pract ; 163: 108148, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32302665

RESUMO

AIMS: Hypoglycemia is one of the most important complications associated with Ramadan fasting in people with type 2 diabetes. LixiRam (NCT02941367) was the first randomized trial comparing safety and efficacy of lixisenatide + basal insulin (BI) vs. sulphonylurea + BI in people with type 2 diabetes who fast during Ramadan. This post hoc analysis focuses on the LixiRam study population from India. METHODS: Adults with type 2 diabetes insufficiently controlled with sulphonylurea + BI ± another oral anti-hyperglycemic drug were randomized 1:1 to receive lixisenatide + BI or to continue sulphonylurea + BI treatment. RESULTS: In total, 150 participants were randomized in India. One participant (1.3%) with lixisenatide + BI vs. 5 participants (6.8%) with sulphonylurea + BI experienced ≥1 documented symptomatic hypoglycemic event during the Ramadan fast (odds ratio [OR]: 0.22; 95% confidence interval [CI]: 0.02-1.93). Incidence of any hypoglycemia was numerically lower with lixisenatide + BI vs. sulphonylurea + BI during Ramadan fasting (1.3% [1/75] vs. 14.7% [11/75], respectively; OR: 0.09; 95% CI: 0.01-0.69). No new safety signals were identified. CONCLUSIONS: A combination of lixisenatide prandial GLP1-RA + BI may be a suitable treatment option for people with type 2 diabetes who elect to fast during Ramadan. Clinical Trial Registry: clinicaltrials.gov (NCT02941367).


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/epidemiologia , Hipoglicemiantes/uso terapêutico , Insulinas/uso terapêutico , Peptídeos/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 2/etnologia , Feminino , Humanos , Hipoglicemiantes/farmacologia , Incidência , Índia , Insulinas/farmacologia , Islamismo , Masculino , Pessoa de Meia-Idade , Peptídeos/farmacologia
16.
Nucleic Acids Res ; 48(10): 5540-5554, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32347931

RESUMO

In the fight against antimicrobial resistance, the bacterial DNA sliding clamp, ß-clamp, is a promising drug target for inhibition of DNA replication and translesion synthesis. The ß-clamp and its eukaryotic homolog, PCNA, share a C-terminal hydrophobic pocket where all the DNA polymerases bind. Here we report that cell penetrating peptides containing the PCNA-interacting motif APIM (APIM-peptides) inhibit bacterial growth at low concentrations in vitro, and in vivo in a bacterial skin infection model in mice. Surface plasmon resonance analysis and computer modeling suggest that APIM bind to the hydrophobic pocket on the ß-clamp, and accordingly, we find that APIM-peptides inhibit bacterial DNA replication. Interestingly, at sub-lethal concentrations, APIM-peptides have anti-mutagenic activities, and this activity is increased after SOS induction. Our results show that although the sequence homology between the ß-clamp and PCNA are modest, the presence of similar polymerase binding pockets in the DNA clamps allows for binding of the eukaryotic binding motif APIM to the bacterial ß-clamp. Importantly, because APIM-peptides display both anti-mutagenic and growth inhibitory properties, they may have clinical potential both in combination with other antibiotics and as single agents.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , DNA Polimerase III/antagonistas & inibidores , Peptídeos/química , Peptídeos/farmacologia , Animais , Antibacterianos/metabolismo , Antibacterianos/uso terapêutico , DNA Polimerase III/química , Replicação do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA , Feminino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos Endogâmicos BALB C , Mutagênese/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Antígeno Nuclear de Célula em Proliferação/metabolismo , Domínios e Motivos de Interação entre Proteínas , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus epidermidis/genética , Staphylococcus epidermidis/crescimento & desenvolvimento
17.
Am J Gastroenterol ; 115(6): 895-905, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32324606

RESUMO

OBJECTIVES: Chronic idiopathic constipation (CIC) is characterized by unsatisfactory defecation and difficult or infrequent stools. CIC affects 9%-20% of adults in the United States, and although prevalent, gaps in knowledge remain regarding CIC healthcare seeking and medication use in the community. We recruited a population-based sample to determine the prevalence and predictors of (i) individuals having discussed their constipation symptoms with a healthcare provider and (ii) the use of constipation therapies. METHODS: We recruited a representative sample of Americans aged 18 years or older who had experienced constipation. Those who met the Rome IV criteria for irritable bowel syndrome and opioid-induced constipation were excluded. The survey included questions on constipation severity, healthcare seeking, and the use of constipation medications. We used multivariable regression methods to adjust for confounders. RESULTS: Overall, 4,702 participants had experienced constipation (24.0% met the Rome IV CIC criteria). Among all respondents with previous constipation, 37.6% discussed their symptoms with a clinician (primary care provider 87.6%, gastroenterologist 26.0%, and urgent care/emergency room physician 7.7%). Age, sex, race/ethnicity, marital status, employment status, having a source of usual care, insurance status, comorbidities, locus of control, and constipation severity were associated with seeking care (P < 0.05). Overall, 47.8% of respondents were taking medication to manage their constipation: over-the-counter medication(s) only, 93.5%; prescription medication(s) only, 1.3%; and both over-the-counter medication(s) and prescription medication(s), 5.2%. DISCUSSION: We found that 3 of 5 Americans with constipation have never discussed their symptoms with a healthcare provider. Furthermore, the use of prescription medications for managing constipation symptoms is low because individuals mainly rely on over-the-counter therapies.


Assuntos
Constipação Intestinal/tratamento farmacológico , Laxantes/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Fatores Etários , Bisacodil/uso terapêutico , Doença Crônica , Colonoscopia/estatística & dados numéricos , Constipação Intestinal/fisiopatologia , Fibras na Dieta/uso terapêutico , Ácido Dioctil Sulfossuccínico/uso terapêutico , Serviço Hospitalar de Emergência , Emprego , Grupos Étnicos/estatística & dados numéricos , Feminino , Gastroenterologistas , Fármacos Gastrointestinais/uso terapêutico , Agonistas da Guanilil Ciclase C/uso terapêutico , Humanos , Seguro Saúde/estatística & dados numéricos , Controle Interno-Externo , Lactulose/uso terapêutico , Masculino , Estado Civil/estatística & dados numéricos , Pessoa de Meia-Idade , Medicamentos sem Prescrição/uso terapêutico , Peptídeos/uso terapêutico , Médicos de Atenção Primária , Polietilenoglicóis/uso terapêutico , Senosídeos/uso terapêutico , Índice de Gravidade de Doença , Fatores Sexuais , Tensoativos/uso terapêutico , Inquéritos e Questionários , Estados Unidos
18.
ACS Nano ; 14(4): 5143-5147, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32286790

RESUMO

Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.


Assuntos
Betacoronavirus/efeitos dos fármacos , Química Computacional , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Simulação de Dinâmica Molecular , Peptídeos , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Humanos , Pandemias , Peptídeos/química , Peptídeos/uso terapêutico , Peptidil Dipeptidase A/efeitos dos fármacos , Conformação Proteica , Conformação Proteica em alfa-Hélice
19.
Physiol Genomics ; 52(5): 217-221, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275178
20.
Adv Exp Med Biol ; 1248: 531-546, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185724

RESUMO

Peptides, as a large group of molecules, are composed of amino acid residues and can be divided into linear or cyclic peptides according to the structure. Over 13,000 molecules of natural peptides have been found and many of them have been well studied. In artificial peptide libraries, the number of peptide diversity could be up to 1 × 1013. Peptides have more complex structures and higher affinity to target proteins comparing with small molecular compounds. Recently, the development of targeting cancer immune checkpoint (CIP) inhibitors is having a very important role in tumor therapy. Peptides targeting ligands or receptors in CIP have been designed based on three-dimensional structures of target proteins or directly selected by random peptide libraries in biological display systems. Most of these targeting peptides work as inhibitors of protein-protein interaction and improve CD8+ cytotoxic T-lymphocyte (CTL) activation in the tumor microenvironment, for example, PKHB1, Ar5Y4 and TPP1. Peptides could be designed to regulate CIP protein degradation in vivo, such as PD-LYSO and PD-PALM. Besides its use in developing therapeutic drugs for targeting CIP, targeting peptides could be used in drug's targeted delivery and diagnosis in tumor immune therapy.


Assuntos
Sistemas de Liberação de Medicamentos , Terapia de Alvo Molecular , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Biblioteca de Peptídeos , Peptídeos/química
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