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1.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 55(10): 757-764, 2020 Oct 09.
Artigo em Chinês | MEDLINE | ID: mdl-33045788

RESUMO

Objective: To investigate the effect of RATEA16 scaffold on the proliferation of human umbilical vein endothelial cells (HUVEC) and the effect of new self-assembling peptide hydrogel (RATEA16) scaffold with vascular endothelial growth factor (VEGF) on promoting angiogenesis. Methods: RATEA16 hydrogel was prepared, then the injectability, microstructure, degradation, biocompatibility of RATEA16 hydrogel were determined. HUVEC were cultured with RATEA16 scaffold to detect cell morphology and proliferation. HUVEC were cultured on RATEA16 scaffold with VEGF for 24 h. The expression of VEGF-A, von Willebrand factor (vWF), matrix metalloproteinase-9 (MMP-9) and platelet endothelial cell adhesion molecule-1 (PECAM-1) were detected by using real-time PCR to evaluate the effects of the scaffold with VEGF system on HUVEC differentiation. Results: The sol-gel transition was completed under neutral condition (pH=7.4) adjusted by Tris-HCl solution. The hydrogel could be easily injected from a syringe. It presented a porous and interconnected internal structure and the porosity of the scaffold was (67.3±9.4)%. After 4 week degradation in vitro, the residual weight was still (82.354±0.006)%, which exhibited slow degradation. HUVEC grew well after being cultured in leach liquor of RATEA16 hydrogel for 24 h, and there was no significant difference in HUVEC cell viability compared with that of the control group (P>0.05). HUVEC encapsulated in RATEA16 hydrogel appeared round in shape and exhibited effectively continuous proliferation. When HUVEC were cultured on RATEA16 hydrogel with VEGF for 24 h, the formation of vascular-like structures was observed. The expression of VEGF-A and MMP-9 was 1.5-2.0 times that of control group, and vWF was 10 times and PECAM-1 was 55 times compared with that of the control group (P<0.05). Conclusions: The RATEA16 hydrogel used in this study could be prepared by simply adjusting pH to neutral. This hydrogel exhibited good biodegradability, slow degradation and injectability. HUVEC might attach and spread in RATEA16 scaffold. The RATEA16 scaffold with VEGF could promote angiogenic differentiation of HUVEC. The novel scaffold is expected to achieve the critical vascularization process in bone tissue regeneration.


Assuntos
Hidrogéis , Fator A de Crescimento do Endotélio Vascular , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos/farmacologia , Veias Umbilicais
2.
Hautarzt ; 71(10): 741-751, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32880662

RESUMO

Melanocortins are peptides that share a common central pharmacophor. Melanin pigmentation of interfollicular epidermis and hair via MC1R remains the key physiologic function of the naturally occurring melanocortin peptides in skin. Moreover, the melanocortins are crucially involved in the ultraviolet light-induced tanning response. Under pathophysiologic conditions, melanocortin peptides induce cutaneous hyperpigmentation, likewise via the MC1R axis, e.g. in patients with Addison's disease, ectopic precursor pro-opiomelanocortin (POMC) syndrome and in those with abnormally elevated melanocortin blood levels. Translational research on α­MSH (melanocyte-stimulating hormones) and their antagonists has further revealed a variety of other biological activities beyond pigmentation. They include cytoprotection, antioxidative effects, regulation of collagen metabolism and fibrosis, sebum production, and cutaneous wound healing. These findings have also promoted the development of novel therapies in clinical dermatology including the exploitation of afamelanotide. In 2015, this agent became the first in-class synthetic α­MSH analogue to be approved in dermatology for the treatment of erythropoetic protoporphyria. In addition to afamelanotide, setmelanotide has recently emerged as a highly selective MC4R agonist useful for the treatment of distinct forms of genetically determined obesity, e.g., POMC deficiency. Future perspectives in dermatology reside in treatment of other difficult-to-treat skin diseases with α­MSH analogues, either with topical or systemic formulations. Moreover, synthetic melanocortin peptide derivatives lacking the central pharmacophor but with maintained anti-inflammatory effects could become a promising strategy for the design of new therapies in dermatology.


Assuntos
Dermatologia/tendências , Melanocortinas/química , Peptídeos/química , Pesquisa Médica Translacional , Humanos , Inflamação/metabolismo , Melanocortinas/farmacologia , Peptídeos/farmacologia , Pró-Opiomelanocortina , Pele/metabolismo , alfa-MSH
3.
F1000Res ; 9: 576, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32802318

RESUMO

Background: There are no known medicines or vaccines to control the COVID-19 pandemic caused by SARS-CoV-2 (nCoV). Antiviral peptides are superior to conventional drugs and may also be effective against COVID-19. Hence, we investigated the SARS-CoV-2 Spike receptor-binding domain (nCoV-RBD) that interacts with hACE2 for viral attachment and entry. Methods: Three strategies and bioinformatics approaches were employed to design potential nCoV-RBD - hACE2 interaction-blocking peptides that may restrict viral attachment and entry. Firstly, the key residues interacting with nCoV-RBD - hACE2 are identified and hACE2 sequence-based peptides are designed. Second, peptides from five antibacterial peptide databases that block nCoV-RBD are identified; finally, a chimeric peptide design approach is used to design peptides that can bind to key nCoV-RBD residues. The final peptides are selected based on their physiochemical properties, numbers and positions of key residues binding, binding energy, and antiviral properties. Results: We found that: (i) three amino acid stretches in hACE2 interact with nCoV-RBD; (ii) effective peptides must bind to three key positions of nCoV-RBD (Gly485/Phe486/Asn487, Gln493, and Gln498/Thr500/Asn501); (iii) Phe486, Gln493, and Asn501 are critical residues; (iv) AC20 and AC23 derived from hACE2 may block two key critical positions; (iv) DBP6 identified from databases can block the three sites of the nCoV-RBD and interacts with one critical position, Gln498; (v) seven chimeric peptides were considered promising, among which cnCoVP-3, cnCoVP-4, and cnCoVP-7 are the top three; and (vi) cnCoVP-4 meets all the criteria and is the best peptide. Conclusions: To conclude, using three different bioinformatics approaches, we identified 17 peptides that can potentially bind to the nCoV-RBD that interacts with hACE2. Binding these peptides to nCoV-RBD may potentially inhibit the virus to access hACE2 and thereby may prevent the infection. Out of 17, 10 peptides have promising potential and need further experimental validation.


Assuntos
Infecções por Coronavirus , Pandemias , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Betacoronavirus , Humanos , Receptores Virais/química
4.
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
5.
SAR QSAR Environ Res ; 31(9): 643-654, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32847369

RESUMO

A quantitative structure-activity relationship (QSAR) model was built from a dataset of 54 peptide-type compounds as SARS-CoV inhibitors. The analysis was executed to identify prominent and hidden structural features that govern anti-SARS-CoV activity. The QSAR model was derived from the genetic algorithm-multi-linear regression (GA-MLR) methodology. This resulted in the generation of a statistically robust and highly predictive model. In addition, it satisfied the OECD principles for QSAR validation. The model was validated thoroughly and fulfilled the threshold values of a battery of statistical parameters (e.g. r 2 = 0.87, Q 2 loo = 0.82). The derived model is successful in identifying many atom-pairs as important structural features that govern the anti-SARS-CoV activity of peptide-type compounds. The newly developed model has a good balance of descriptive and statistical approaches. Consequently, the present work is useful for future modifications of peptide-type compounds for SARS-CoV and SARS-CoV-2 activity.


Assuntos
Antivirais , Betacoronavirus/efeitos dos fármacos , Peptídeos , Relação Quantitativa Estrutura-Atividade , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/enzimologia , Cisteína Endopeptidases , Concentração Inibidora 50 , Modelos Lineares , Estrutura Molecular , Peptídeos/química , Peptídeos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores
6.
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
7.
Nat Commun ; 11(1): 4278, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855388

RESUMO

Activation and migration of endogenous mesenchymal stromal cells (MSCs) are critical for bone regeneration. Here, we report a combinational peptide screening strategy for rapid discovery of ligands that not only bind strongly to osteogenic progenitor cells (OPCs) but also stimulate osteogenic cell Akt signaling in those OPCs. Two lead compounds are discovered, YLL3 and YLL8, both of which increase osteoprogenitor osteogenic differentiation in vitro. When given to normal or osteopenic mice, the compounds increase mineral apposition rate, bone formation, bone mass, and bone strength, as well as expedite fracture repair through stimulated endogenous osteogenesis. When covalently conjugated to alendronate, YLLs acquire an additional function resulting in a "tri-functional" compound that: (i) binds to OPCs, (ii) targets bone, and (iii) induces "pro-survival" signal. These bone-targeted, osteogenic peptides are well suited for current tissue-specific therapeutic paradigms to augment the endogenous osteogenic cells for bone regeneration and the treatment of bone loss.


Assuntos
Anabolizantes/farmacologia , Fraturas Ósseas/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Peptídeos/farmacologia , Células-Tronco/efeitos dos fármacos , Anabolizantes/química , Animais , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Fraturas Ósseas/patologia , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Orquiectomia , Osteogênese/fisiologia , Ovariectomia , Peptídeos/química , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Técnicas de Síntese em Fase Sólida , Células-Tronco/citologia
8.
PLoS One ; 15(8): e0237328, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790707

RESUMO

α-Synuclein (αSyn) fibrils spread from one neuronal cell to another. This prion-like phenomenon is believed to contribute to the progression of the pathology in Parkinson's disease and other synucleinopathies. The binding of αSyn fibrils originating from affected cells to the plasma membrane of naïve cells is key in their prion-like propagation propensity. To interfere with this process, we designed polypeptides derived from proteins we previously showed to interact with αSyn fibrils, namely the molecular chaperone Hsc70 and the sodium/potassium pump NaK-ATPase and assessed their capacity to bind αSyn fibrils and/or interfere with their take-up by cells of neuronal origin. We demonstrate here that polypeptides that coat αSyn fibrils surfaces in such a way that they are changed affect αSyn fibrils binding to the plasma membrane components and/or their take-up by cells. Altogether our observations suggest that the rationale design of αSyn fibrils polypeptide binders that interfere with their propagation between neuronal cells holds therapeutic potential.


Assuntos
Neurônios/efeitos dos fármacos , Peptídeos/farmacologia , Agregação Patológica de Proteínas/tratamento farmacológico , alfa-Sinucleína/metabolismo , Sequência de Aminoácidos , Amiloide/antagonistas & inibidores , Amiloide/metabolismo , Animais , Linhagem Celular , Proteínas de Choque Térmico HSC70/química , Proteínas de Choque Térmico HSC70/metabolismo , Proteínas de Choque Térmico HSC70/farmacologia , Humanos , Camundongos , Modelos Moleculares , Neurônios/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Peptídeos/química , Príons/antagonistas & inibidores , Príons/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/metabolismo , ATPase Trocadora de Sódio-Potássio/química , ATPase Trocadora de Sódio-Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/farmacologia
9.
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
10.
Food Chem ; 333: 127482, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32659671

RESUMO

In order to evaluate differences in the peptide profile and bioactive potential in dairy products, by increasing the protein content and using proteolytic bacteria strain to enable the release of bioactive peptides, a high-protein yogurt with adjunct culture was developed. The effect of protein content, the addition of Lactobacillus helveticus LH-B02, and storage time were evaluated. The qualitative analysis of peptide profile was performed using a mass spectrometry approach (MALDI-ToF-MS), and the potential bioactivity evaluated by ACE inhibition activity. Protein content did not affect the peptide profile in yogurts, and the addition of Lactobacillus helveticus LH-B02 favored the formation of peptides recognized as bioactive, such as αS1-CN f(24-32) and ß-CN f(193-209). Increased protein content and adjunct culture addition increased the ACE inhibitory activity. The combination of both factors had no additional effect on the bioactive potential of yogurts.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Lactobacillus helveticus/metabolismo , Peptídeos/análise , Peptídeos/farmacologia , Iogurte/análise , Iogurte/microbiologia , Animais , Fermentação
11.
Proc Natl Acad Sci U S A ; 117(32): 19168-19177, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719135

RESUMO

The emergence of superbugs developing resistance to antibiotics and the resurgence of microbial infections have led scientists to start an antimicrobial arms race. In this context, we have previously identified an active RiPP, the Ruminococcin C1, naturally produced by Ruminococcus gnavus E1, a symbiont of the healthy human intestinal microbiota. This RiPP, subclassified as a sactipeptide, requires the host digestive system to become active against pathogenic Clostridia and multidrug-resistant strains. Here we report its unique compact structure on the basis of four intramolecular thioether bridges with reversed stereochemistry introduced posttranslationally by a specific radical-SAM sactisynthase. This structure confers to the Ruminococcin C1 important clinical properties including stability to digestive conditions and physicochemical treatments, a higher affinity for bacteria than simulated intestinal epithelium, a valuable activity at therapeutic doses on a range of clinical pathogens, mediated by energy resources disruption, and finally safety for human gut tissues.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Clostridiales/química , Peptídeos/química , Peptídeos/farmacologia , Antibacterianos/isolamento & purificação , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Peptídeos/isolamento & purificação
12.
Aging (Albany NY) ; 12(12): 11263-11276, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32544884

RESUMO

The outbreak of COVID-19 has now become a global pandemic that has severely impacted lives and economic stability. There is, however, no effective antiviral drug that can be used to treat COVID-19 to date. Built on the fact that SARS-CoV-2 initiates its entry into human cells by the receptor binding domain (RBD) of its spike protein binding to the angiotensin-converting enzyme 2 (hACE2), we extended a recently developed approach, EvoDesign, to design multiple peptide sequences that can competitively bind to the SARS-CoV-2 RBD to inhibit the virus from entering human cells. The protocol starts with the construction of a hybrid peptidic scaffold by linking two fragments grafted from the interface of the hACE2 protein (a.a. 22-44 and 351-357) with a linker glycine, which is followed by the redesign and refinement simulations of the peptide sequence to optimize its binding affinity to the interface of the SARS-CoV-2 RBD. The binding experiment analyses showed that the designed peptides exhibited a significantly stronger binding potency to hACE2 than the wild-type hACE2 receptor (with -53.35 vs. -46.46 EvoEF2 energy unit scores for the top designed and wild-type peptides, respectively). This study demonstrates a new avenue to utilize computationally designed peptide motifs to treat the COVID-19 disease by blocking the critical spike-RBD and hACE2 interactions.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Peptídeos/síntese química , Peptídeos/farmacologia , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/fisiologia , Sequência de Aminoácidos , Antivirais , Sítios de Ligação , Desenho de Fármacos , Evolução Molecular , Humanos , Modelos Moleculares , Pandemias , Ligação Proteica , Conformação Proteica , Internalização do Vírus/efeitos dos fármacos
13.
PLoS One ; 15(6): e0232493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511256

RESUMO

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/terapia , Peptídeos/farmacologia , Complicações na Gravidez/tratamento farmacológico , Nascimento Prematuro/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/imunologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Lipopolissacarídeos , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gravidez , Complicações na Gravidez/imunologia , Nascimento Prematuro/imunologia
14.
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
15.
Drugs R D ; 20(3): 161-169, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32592145

RESUMO

BACKGROUND AND OBJECTIVE: Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection. METHODS: Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. RESULTS: We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus. CONCLUSION: Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Peptídeos/farmacologia , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/metabolismo , Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Vacinas Virais/farmacologia
16.
Am J Physiol Heart Circ Physiol ; 319(1): H171-H182, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502377

RESUMO

The role of the ASIC1a in evoking the exercise pressor reflex in rats with simulated peripheral artery disease is unknown. This prompted us to determine whether ASIC1a plays a role in evoking the exaggerated exercise pressor reflex in decerebrated rats with simulated peripheral artery disease. To simulate peripheral artery disease, we ligated the left femoral artery 72 h before the experiment. The right femoral artery was freely perfused and used as a control. To test our hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles with and without the femoral artery ligated on the reflex pressor responses to 1) static contraction of the triceps surae muscles, 2) calcaneal tendon stretch, and 3) intra-arterial injection of diprotonated phosphate (pH 6.0). We found that the ASIC1a blockers psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 µg/kg) decreased the pressor responses to static contraction as well as the peak pressor responses to injection of diprotonated phosphate when these responses were evoked from the freely perfused hindlimb. In contrast, ASIC1a blockers only decreased the peak pressor responses evoked by injection of diprotonated phosphate in the hindlimb circulation with simulated peripheral artery disease. This inhibitory effect was less than the one measured from the healthy hindlimb. Independently of the hindlimb of interest, ASIC1a blockers had no effect on the pressor responses to tendon stretch. Our results do not support the hypothesis that ASIC1a play a role in evoking the exercise pressor reflex arising from a hindlimb with simulated peripheral artery disease.NEW & NOTEWORTHY The role of ASIC1a in evoking the metabolic component of the exercise pressor reflex in peripheral artery disease is unknown. Using a within-rat experimental design, we found that the contribution of ASIC1a decreased in a rat model of peripheral artery disease. These results have key implications to help finding better treatments and improve morbidity, quality of life, and mortality in patients with peripheral artery disease.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Contração Muscular , Doença Arterial Periférica/metabolismo , Esforço Físico , Reflexo , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Animais , Venenos Elapídicos/farmacologia , Artéria Femoral/fisiopatologia , Masculino , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Peptídeos/farmacologia , Doença Arterial Periférica/fisiopatologia , Ratos , Ratos Sprague-Dawley , Venenos de Aranha/farmacologia , Tendões/fisiopatologia
17.
Life Sci ; 257: 118025, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32598933

RESUMO

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists have emerged as treatment options for reversing diabetes and obesity. Here, we screened the high potency receptor-biased GLP-1R agonists via a newly designed high-throughput GLP-1R extracellular domain (ECD)-based system and demonstrated its in vitro and in vivo therapeutic characters. METHODS: Twelve 9-mer peptides (named XEL1-XEL12) which were screened from a large phage-displayed peptide library were fused to the N-terminus of GIP (3-30) to generate another twelve fusion peptides, termed XEL13-24. Using the six lysine-altered XEL17 as leading sequences, eighteen fatty chain modified fusion peptides were further assessed via in vitro GLP-1R/GIPR-based cell assay. Moreover, the acute and long-acting in vivo effects of selected candidate on diabetic db/db mice and diet-induced obesity (DIO) rats were both carefully evaluated. RESULTS: XEL17 exhibited balanced activation potency on GLP-1R/GIPR in stable cell lines, and further assessment was performed to evaluate the XEL32, a fatty chain modified XEL17 derivative. Preclinical pharmacodynamic results in diabetic db/db mice demonstrated that XEL32 held outstanding insulinotropic and glucose-lowering activities. In addition, protracted antidiabetic effects of XEL32 were also proved by the hypoglycemic test and multiple oral glucose tolerance test. Furthermore, chronic treatment of XEL32 in DIO rats exhibited outstanding beneficial effects on body weight control, fat loss, food intake control, hemoglobin A1C (HbA1C) reduction as well as the glucose tolerance. CONCLUSIONS: XEL32, as a novel GLP-1/GIP dual receptor agonist, may supply efficient glycemic control and weight loss.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos/farmacologia , Receptores dos Hormônios Gastrointestinais/metabolismo , Perda de Peso/efeitos dos fármacos , Animais , Glicemia/metabolismo , China , Diabetes Mellitus/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/efeitos dos fármacos , Teste de Tolerância a Glucose , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Obesidade/metabolismo , Ratos , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/efeitos dos fármacos
18.
Proc Natl Acad Sci U S A ; 117(27): 16043-16054, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571919

RESUMO

In the indeterminate nodules of a model legume Medicago truncatula, ∼700 nodule-specific cysteine-rich (NCR) peptides with conserved cysteine signature are expressed. NCR peptides are highly diverse in sequence, and some of these cationic peptides exhibit antimicrobial activity in vitro and in vivo. However, there is a lack of knowledge regarding their structural architecture, antifungal activity, and modes of action against plant fungal pathogens. Here, the three-dimensional NMR structure of the 36-amino acid NCR044 peptide was solved. This unique structure was largely disordered and highly dynamic with one four-residue α-helix and one three-residue antiparallel ß-sheet stabilized by two disulfide bonds. NCR044 peptide also exhibited potent fungicidal activity against multiple plant fungal pathogens, including Botrytis cinerea and three Fusarium spp. It inhibited germination in quiescent spores of B. cinerea In germlings, it breached the fungal plasma membrane and induced reactive oxygen species. It bound to multiple bioactive phosphoinositides in vitro. Time-lapse confocal and superresolution microscopy revealed strong fungal cell wall binding, penetration of the cell membrane at discrete foci, followed by gradual loss of turgor, subsequent accumulation in the cytoplasm, and elevated levels in nucleoli of germlings. Spray-applied NCR044 significantly reduced gray mold disease symptoms caused by the fungal pathogen B. cinerea in tomato and tobacco plants, and postharvest products. Our work illustrates the antifungal activity of a structurally unique NCR peptide against plant fungal pathogens and paves the way for future development of this class of peptides as a spray-on fungistat/fungicide.


Assuntos
Antifúngicos/farmacologia , Peptídeos/metabolismo , Peptídeos/farmacologia , Doenças das Plantas/prevenção & controle , Proteínas de Plantas/metabolismo , Proteínas de Plantas/farmacologia , Simbiose , Sequência de Aminoácidos , Botrytis/metabolismo , Membrana Celular/metabolismo , Parede Celular/metabolismo , Cisteína/química , Fusarium/metabolismo , Lycopersicon esculentum/metabolismo , Lycopersicon esculentum/microbiologia , Espectroscopia de Ressonância Magnética , Medicago truncatula/microbiologia , Pichia/metabolismo , Doenças das Plantas/microbiologia , Tabaco/metabolismo , Tabaco/microbiologia
19.
Food Chem ; 331: 127350, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32590267

RESUMO

Fish by-products are excellent sources of collagen. Acid-soluble collagen (ASC) derived from a mixed by-product of different fish species was hydrolyzed to obtain peptide fractions and evaluate their biological and functional activities. All fractions obtained (F1: ≥30, F2: 10-30, F3: 5-10, F4: 1-5, and F5: ≤1kDa) exhibited antioxidant activity at concentrations of 5, 10, and 15 mg/mL. However, F5 registered the highest reducing power (absorbance 0.366) and hydroxyl-radical-scavenging activity (91%) at 15 mg/mL; whereas the highest DPPH scavenging activity (81%) was also detected in F5 at 5 mg/mL. The solubility of F1, F2, and F3 was ≥ 95% at pH 7. The highest foaming capacity (78%), foaming stability (60%), and emulsion stability index (42 min) were registered for F1. However, the highest emulsifying activity index (130 m2/g) was for F3. These results place collagen obtained from a mixed by-product of different fish species as a potential biotechnological alternative for the industry.


Assuntos
Antioxidantes/farmacologia , Colágeno/química , Produtos Pesqueiros , Proteínas de Peixes/química , Peptídeos/química , Peptídeos/farmacologia , Aminoácidos/análise , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Emulsificantes/química , Proteínas de Peixes/farmacologia , Depuradores de Radicais Livres/química , Concentração de Íons de Hidrogênio , Hidrólise , Radical Hidroxila/química , Hidrolisados de Proteína/química , Solubilidade
20.
Nat Struct Mol Biol ; 27(7): 653-659, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541896

RESUMO

Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM structure of recombinant full-length hIAPP fibrils. The fibril is composed of two symmetrically related protofilaments with ordered residues 14-37. Our hIAPP fibril structure (i) supports the previous hypothesis that residues 20-29 constitute the core of the hIAPP amyloid; (ii) suggests a molecular mechanism for the action of the hIAPP hereditary mutation S20G; (iii) explains why the six residue substitutions in rodent IAPP prevent aggregation; and (iv) suggests regions responsible for the observed hIAPP cross-seeding with ß-amyloid. Furthermore, we performed structure-based inhibitor design to generate potential hIAPP aggregation inhibitors. Four of the designed peptides delay hIAPP aggregation in vitro, providing a starting point for the development of T2D therapeutics and proof of concept that the capping strategy can be used on full-length cryo-EM fibril structures.


Assuntos
Diabetes Mellitus Tipo 2/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/antagonistas & inibidores , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Peptídeos/química , Amiloide/química , Animais , Microscopia Crioeletrônica , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Modelos Moleculares , Mutação , Peptídeos/farmacologia , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Roedores
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