RESUMO
The oral cavity is a frequent site for head and neck cancers, which rank as the sixth most common cancer globally, with a 5-year survival rate slightly over 50%. Current treatments are limited, and resistance to therapy remains a significant clinical obstacle. IsCT1, a membrane-active peptide derived from the venom of the scorpion Opisthacanthus madagascariensis, has shown antitumor effects in various cancer cell lines, including breast cancer and chronic myeloid leukemia. However, its hemolytic action limits its potential therapeutic use. This study aims to assess the antitumor and antiproliferative activities of synthetic peptides derived from IsCT1 (IsCT-P, AC-AFPK-IsCT1, AFPK-IsCT1, AC-KKK-IsCT1, and KKK-IsCT1) in the context of oral squamous cell carcinoma. We evaluated the cytotoxic effects of these peptides on tongue squamous cell carcinoma cells and normal cells, as well as their impact on cell cycle phases, the expression of proliferation markers, modulators of cell death pathways, and mitochondrial potential. Our results indicate that the IsCT1 derivatives IsCT-P and AC-AFPK-IsCT1 possess cytotoxic properties towards squamous cell carcinoma cells, reducing mitochondrial membrane potential and the proliferative index. The treatment of cancer cells with AC-AFPK-IsCT1 led to a positive modulation of pro-apoptotic markers p53 and caspases 3 and 8, a decrease in PCNA and Cyclin D1 expression, and cell cycle arrest in the S phase. Notably, contrary to the parental IsCT1 peptide, AC-AFPK-IsCT1 did not exhibit hemolytic activity or cytotoxicity towards normal cells. Therefore, AC-AFPK-IsCT1 might be a viable therapeutic option for head and neck cancer treatment.
Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Proliferação de Células , Neoplasias Bucais , Venenos de Escorpião , Humanos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Venenos de Escorpião/farmacologia , Venenos de Escorpião/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/síntese química , Apoptose/efeitos dos fármacos , Escorpiões/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacosRESUMO
BACKGROUND/OBJECTIVES: The oral administration of hydrolyzed collagen peptides is a scientifically validated intervention for enhancing skeletal muscle health and performance. This integrative review consolidates the evidence supporting the use of low molecular weight collagen peptides (2000-3500 daltons) for their superior bioavailability and absorption. Our objective was to review the effects of collagen peptide or hydrolyzed collagen supplementation on muscle damage, recovery, and construction related to physical exercise. METHODS: A bibliographic search was conducted in major English-language databases, including PubMed/Medline, using terms like "Peptides Collagen and Damage" and "collagen peptides AND Soreness Muscle". This review followed PRISMA guidelines, with bias risk assessed via the PEDro scale. The inclusion criteria were (a) randomized clinical trials, (b) randomized studies in humans with a control or placebo group, (c) studies assessing muscle damage or delayed onset muscle soreness via physiological markers or strength performance tests, and (d) studies using hydrolyzed collagen or collagen peptides. RESULTS: Initially, 752 articles were identified. After applying the inclusion and exclusion criteria, including duplicate removal, eight articles with 286 participants were included. Of these, 130 participants received collagen peptide supplementation, while 171 received a placebo or control. CONCLUSION: This integrative review supports the potential of collagen peptide supplementation to mitigate muscle stress from acute strenuous resistance training. However, due to the methodological heterogeneity among the studies, further clinical trials are needed to clarify the mechanisms underlying muscle improvement with collagen supplementation.
Assuntos
Colágeno , Suplementos Nutricionais , Músculo Esquelético , Mialgia , Humanos , Músculo Esquelético/efeitos dos fármacos , Mialgia/tratamento farmacológico , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Treinamento Resistido , Fadiga Muscular/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Força Muscular/efeitos dos fármacos , Masculino , Adulto , Feminino , Exercício FísicoRESUMO
Recent research has demonstrated the increasing interest in using insects for the extraction of bioactive compounds, particularly peptides. These compounds offer a spectrum of beneficial physiological effects. The aim of this study was to standardize a methodology for obtaining bioactive peptides from Tenebrio molitor and evaluate its physicochemical characterization, antioxidant, and antimicrobial potential. Six assays were carried out to hydrolyse larvae protein, with variations in Alcalase concentration (0.04 to 0.08%) and reaction time (3 to 8 h). The results indicated that the process applied to defatted mealworm flour was effective in reducing lipids by 82.5%. Consequently, it was an observed increase of 38.4% in protein content. Additionally, an increase in glycogen content was found in defatted mealworm flour (177 µmol glucose g-1 sample) and peptides (152.81 µmol glucose g-1 sample). The degree of hydrolysis was higher in assays with longer hydrolysis durations (8.14 - 8.38%). The antioxidant capacity was 12 to 14% lower in assays with an incubation time of 8h. In this sense, the methodology proposed in the present study proved to be efficient in obtaining bioactive peptides from T. molitor.
Assuntos
Antioxidantes , Peptídeos , Tenebrio , Tenebrio/química , Animais , Antioxidantes/farmacologia , Antioxidantes/análise , Antioxidantes/química , Peptídeos/análise , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/isolamento & purificação , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/análise , Testes de Sensibilidade MicrobianaRESUMO
Bioinformatics has emerged as a valuable tool for screening drugs and understanding their effects. This systematic review aimed to evaluate whether in silico studies using anti-obesity peptides targeting therapeutic pathways for obesity, when subsequently evaluated in vitro and in vivo, demonstrated effects consistent with those predicted in the computational analysis. The review was framed by the question: "What peptides or proteins have been used to treat obesity in in silico studies?" and structured according to the acronym PECo. The systematic review protocol was developed and registered in PROSPERO (CRD42022355540) in accordance with the PRISMA-P, and all stages of the review adhered to these guidelines. Studies were sourced from the following databases: PubMed, ScienceDirect, Scopus, Web of Science, Virtual Heath Library, and EMBASE. The search strategies resulted in 1015 articles, of which, based on the exclusion and inclusion criteria, 7 were included in this systematic review. The anti-obesity peptides identified originated from various sources including bovine alpha-lactalbumin from cocoa seed (Theobroma cacao L.), chia seed (Salvia hispanica L.), rice bran (Oryza sativa), sesame (Sesamum indicum L.), sea buckthorn seed flour (Hippophae rhamnoides), and adzuki beans (Vigna angularis). All articles underwent in vitro and in vivo reassessment and used molecular docking methodology in their in silico studies. Among the studies included in the review, 46.15% were classified as having an "uncertain risk of bias" in six of the thirteen criteria evaluated. The primary target investigated was pancreatic lipase (n = 5), with all peptides targeting this enzyme demonstrating inhibition, a finding supported both in vitro and in vivo. Additionally, other peptides were identified as PPARγ and PPARα agonists (n = 2). Notably, all peptides exhibited different mechanisms of action in lipid metabolism and adipogenesis. The findings of this systematic review underscore the effectiveness of computational simulation as a screening tool, providing crucial insights and guiding in vitro and in vivo investigations for the discovery of novel anti-obesity peptides.
Assuntos
Simulação por Computador , Obesidade , Peptídeos , Animais , Humanos , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Biologia Computacional , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Peptídeos/química , Peptídeos/farmacologiaRESUMO
BACKGROUND: Kefir is a complex microbial community that plays a critical role in the fermentation and production of bioactive peptides, and has health-improving properties. The composition of kefir can vary by geographic localization and weather, and this paper focuses on a Brazilian sample and continues previous work that has successful anti-Alzheimer properties. In this study, we employed shotgun metagenomics and peptidomics approaches to characterize Brazilian kefir further. RESULTS: We successfully assembled the novel genome of Lactobacillus kefiranofaciens (LkefirU) and conducted a comprehensive pangenome analysis to compare it with other strains. Furthermore, we performed a peptidome analysis, revealing the presence of bioactive peptides encrypted by L. kefiranofaciens in the Brazilian kefir sample, and utilized in silico prospecting and molecular docking techniques to identify potential anti-Alzheimer peptides, targeting ß-amyloid (fibril and plaque), BACE, and acetylcholinesterase. Through this analysis, we identified two peptides that show promise as compounds with anti-Alzheimer properties. CONCLUSIONS: These findings not only provide insights into the genome of L. kefiranofaciens but also serve as a promising prototype for the development of novel anti-Alzheimer compounds derived from Brazilian kefir.
Assuntos
Doença de Alzheimer , Genoma Bacteriano , Kefir , Lactobacillus , Microbiota , Peptídeos , Kefir/microbiologia , Lactobacillus/genética , Brasil , Peptídeos/química , Peptídeos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Metagenômica/métodosRESUMO
The kallikrein-related peptidase KLK2 has restricted expression in the prostate luminal epithelium, and its protein target is unknown. The present work reports the hydrolytic activities of KLK2 on libraries of fluorescence resonance energy-transfer peptides from which the sequence SYRIF was the most susceptible substrate for KLK2. The sequence SYRIF is present at the extracellular N-terminal segment (58SYRIF63Q) of IL-10R2. KLK2 was fully active at pH 8.0-8.2, found only in prostate inflammatory conditions, and strongly activated by sodium citrate and glycosaminoglycans, the quantities and structures controlled by prostate cells. Bone-marrow-derived macrophages (BMDM) have IL-10R2 expressed on the cell surface, which is significantly reduced after KLK2 treatment, as determined by flow cytometry (FACS analysis). The IL-10 inhibition of the inflammatory response to LPS/IFN-γ in BMDM cells due to decreased nitric oxide, TNF-α, and IL-12 p40 levels is significantly reduced upon treatment of these cells with KLK2. Similar experiments with KLK3 did not show these effects. These observations indicate that KLK2 proteolytic activity plays a role in prostate inflammation and makes KLK2 a promising target for prostatitis treatment.
Assuntos
Calicreínas , Humanos , Masculino , Calicreínas/metabolismo , Calicreínas/química , Arginina/metabolismo , Arginina/química , Próstata/metabolismo , Próstata/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Animais , Camundongos , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/metabolismo , Domínios Proteicos , Interleucina-10/metabolismo , Especificidade por SubstratoRESUMO
With the emergence of multidrug-resistant microorganisms, microbial agents have become a serious global threat, affecting human health and various plants. Therefore, new therapeutic alternatives, such as chitin-binding proteins, are necessary. Chitin is an essential component of the fungal cell wall, and chitin-binding proteins exhibit antifungal activity. In the present study, chitin-binding peptides isolated from Capsicum chinense seeds were characterized and evaluated for their in vitro antimicrobial effect against the growth of Candida and Fusarium fungi. Proteins were extracted from the seeds and subsequently the chitin-binding proteins were separated by chitin affinity chromatography. After chromatography, two fractions, Cc-F1 (not retained on the column) and Cc-F2 (retained on the column), were obtained. Electrophoresis revealed major protein bands between 6.5 and 26.6 kDa for Cc-F1 and only a ~ 6.5 kDa protein band for Cc-F2, which was subsequently subjected to mass spectrometry. The protein showed similarity with hevein-like and endochitinase and was then named Cc-Hev. Data are available via ProteomeXchange with identifier PXD054607. Next, we predicted the three-dimensional structure of the peptides and performed a peptide docking with (NAG)3. Subsequently, growth inhibition assays were performed to evaluate the ability of the peptides to inhibit microorganism growth. Cc-Hev inhibited the growth of C. albicans (up to 75% inhibition) and C. tropicalis (100% inhibition) and induced a 65% decrease in cell viability for C. albicans and 100% for C. tropicalis. Based on these results, new techniques to combat fungal diseases could be developed through biotechnological applications; therefore, further studies are needed.
Assuntos
Antifúngicos , Candida , Capsicum , Quitina , Quitinases , Fusarium , Sementes , Sementes/química , Antifúngicos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/química , Antifúngicos/metabolismo , Quitina/metabolismo , Quitina/farmacologia , Fusarium/efeitos dos fármacos , Quitinases/farmacologia , Quitinases/metabolismo , Quitinases/química , Quitinases/isolamento & purificação , Candida/efeitos dos fármacos , Candida/enzimologia , Lectinas de Plantas/farmacologia , Lectinas de Plantas/química , Lectinas de Plantas/isolamento & purificação , Testes de Sensibilidade Microbiana , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/metabolismo , Simulação de Acoplamento Molecular , Proteínas de Plantas/farmacologia , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/metabolismo , Peptídeos Catiônicos AntimicrobianosRESUMO
Bioinformatics has expedited the screening of new efficient therapeutic agents for diseases such as diabetes mellitus (DM). The objective of this systematic review (SR) was to understand naturally occurring proteins and peptides studied in silico and subsequently reevaluated in vivo for treating DM, guided by the question: which peptides or proteins have been studied in silico for the treatment of diabetes mellitus? The RS protocol was registered in the International Prospective Register of Systematic Reviews database. Articles meeting the eligibility criteria were selected from the PubMed, ScienceDirect, Scopus, Web of Science, Virtual Health Library (VHL), and EMBASE databases. Five studies that investigated peptides or proteins analyzed in silico and in vivo were selected. Risk of bias assessment was conducted using the adapted Strengthening the Reporting of Empirical Simulation Studies (STRESS) tool. A diverse range of assessed proteins and/or peptides that had a natural origin were investigated in silico and corresponding in vivo reevaluation demonstrated reductions in glycemia and/or insulin, morphological enhancements in pancreatic ß cells, and alterations in the gene expression of markers associated with DM. The in silico studies outlined offer crucial insights into therapeutic strategies for DM, along with promising leads for screening novel therapeutic agents in future trials.
Assuntos
Simulação por Computador , Diabetes Mellitus , Peptídeos , Animais , Humanos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Biologia Computacional/métodos , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , ProteínasRESUMO
Dengue, caused by the dengue virus (DENV), is a global health threat transmitted by Aedes mosquitoes, resulting in 400 million cases annually. The disease ranges from mild to severe, with potential progression to hemorrhagic dengue. Current research is focused on natural antivirals due to challenges in vector control. This study evaluates the antiviral potential of peptides derived from the microalgae Phaeodactylum tricornutum, known for its bioactive compounds. Microalgae were cultivated under controlled conditions, followed by protein extraction and hydrolysis to produce four peptide fractions. These fractions were assessed for cytotoxicity via the MTT assay and antiviral activity against DENV serotype 2 using flow cytometry and plaque formation assays. The 10-30 kDa peptide fraction, at 150 and 300 µg/mL concentrations, demonstrated no cytotoxicity and significantly reduced the percentage of infected cells and viral titers. These findings suggest that peptides derived from Phaeodactylum tricornutum exhibit promising antiviral activity against dengue virus serotype 2, potentially contributing to developing new therapeutic approaches for dengue.
Assuntos
Antivirais , Vírus da Dengue , Microalgas , Vírus da Dengue/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Animais , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/química , Dengue/tratamento farmacológico , Dengue/virologia , Peptídeos/farmacologia , Peptídeos/química , Sorogrupo , Chlorocebus aethiops , Humanos , Aedes/efeitos dos fármacos , Células VeroRESUMO
Epilepsy, a neurological disorder characterized by excessive neuronal activity and synchronized electrical discharges, ranks among the most prevalent global neurological conditions. Despite common use, antiepileptic drugs often result in adverse effects and lack effectiveness in controlling seizures in temporal lobe epilepsy (TLE) patients. Recent research explored the potential of occidentalin-1202, a peptide inspired by Polybia occidentalis venom, in safeguarding Wistar rats from chemically induced seizures. The present study evaluated the new analog from occidentalin-1202 named NOR-1202 using acute and chronic pilocarpine-induced models and an acute kainic acid (KA) male mice model. NOR-1202 was administered through the intracerebroventricular (i.c.v.), subcutaneous, or intraperitoneal routes, with stereotaxic procedures for the i.c.v. injection. In the acute pilocarpine-induced model, NOR-1202 (i.c.v.) protected against generalized seizures and mortality but lacked systemic antiepileptic activity. In the KA model, it did not prevent generalized seizures but improved survival. In the chronic TLE model, NOR-1202's ED50 did not differ significantly from the epileptic or healthy groups regarding time spent in spontaneous recurrent seizures during the five-day treatment. However, the NOR-1202 group exhibited more seizures than the healthy group on the second day of treatment. In summary, NOR-1202 exhibits antiepileptic effects against chemoconvulsant-induced seizures, but no effect was observed when administered systemically.
Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Convulsões , Animais , Masculino , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Camundongos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Pilocarpina , Ácido Caínico/análogos & derivados , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptídeos/administração & dosagem , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/induzido quimicamenteRESUMO
Multifunctional peptides derived from various food sources, including ancestral grains, hold significant promise for managing metabolic syndrome. These bioactive peptides exhibit diverse properties that collectively contribute to improving the components of metabolic syndrome. In this study, we investigated the in vitro multifunctionality of six peptides (PW, PM, SW, PPG, PW, and IW) identified through in silico analysis and chemically synthesized. These peptides were evaluated for their potential to address metabolic syndrome-related activities such as antidiabetic, antiobesity, antihypertensive, and antioxidative properties. Assessment included their capacity to inhibit key enzymes associated with these activities, as well as their free radical scavenging and cellular antioxidative activities. Principal component analysis was employed to cluster the peptides according to their multifunctionality. Our results revealed that peptides containing tryptophan (SW, PW, and IW) exhibited the most promising multifunctional attributes, with SW showing particularly high potential. This multifunctional peptide represents a promising avenue for addressing metabolic syndrome.
Assuntos
Síndrome Metabólica , Peptídeos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologiaRESUMO
Previous reports have demonstrated that the peptide derived from LfcinB, R-1-R, exhibits anti-Candida activity, which is enhanced when combined with an extract from the Bidens pilosa plant. However, the mechanism of action remains unexplored. In this research, a proteomic study was carried out, followed by a bioinformatic analysis and biological assays in both the SC5314 strain and a fluconazole-resistant isolate of Candida albicans after incubation with R-1-R. The proteomic data revealed that treatment with R-1-R led to the up-regulation of most differentially expressed proteins compared to the controls in both strains. These proteins are primarily involved in membrane and cell wall biosynthesis, membrane transport, oxidative stress response, the mitochondrial respiratory chain, and DNA damage response. Additionally, proteomic analysis of the C. albicans parental strain SC5314 treated with R-1-R combined with an ethanolic extract of B. pilosa was performed. The differentially expressed proteins following this combined treatment were involved in similar functional processes as those treated with the R-1-R peptide alone but were mostly down-regulated (data are available through ProteomeXchange with identifier PXD053558). Biological assays validated the proteomic results, evidencing cell surface damage, reactive oxygen species generation, and decreased mitochondrial membrane potential. These findings provide insights into the complex antifungal mechanisms of the R-1-R peptide and its combination with the B. pilosa extract, potentially informing future studies on natural product derivatives.
Assuntos
Antifúngicos , Bidens , Candida albicans , Extratos Vegetais , Proteômica , Antifúngicos/farmacologia , Proteômica/métodos , Bidens/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Candida albicans/efeitos dos fármacos , Sinergismo Farmacológico , Proteínas Fúngicas/metabolismo , Peptídeos/farmacologia , Peptídeos/química , Testes de Sensibilidade Microbiana , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologiaRESUMO
Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22-46 of the ACE2 alpha-helix α1) implicated in the S1 receptor-binding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells in vitro. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix α1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S1 RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix α1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the in vitro viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against in vivo SARS-CoV-2 infection and is effective for the treatment of COVID-19.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Peptídeos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Humanos , Animais , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Camundongos , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/uso terapêutico , Tratamento Farmacológico da COVID-19 , Antivirais/farmacologia , Antivirais/química , Linhagem Celular , Pneumonia/tratamento farmacológico , Pneumonia/virologia , Pneumonia/prevenção & controle , Pulmão/virologia , Pulmão/patologia , FemininoRESUMO
Skin wound healing is coordinated by a delicate balance between proinflammatory and anti-inflammatory responses, which can be affected by opportunistic pathogens and metabolic or vascular diseases. Several antimicrobial peptides (AMPs) possess immunomodulatory properties, suggesting their potential to support skin wound healing. Here, we evaluated the proregenerative activity of three recently described AMPs (Clavanin A, Clavanin-MO, and Mastoparan-MO). Human primary dermal fibroblasts (hFibs) were used to determine peptide toxicity and their capacity to induce cell proliferation and migration. Furthermore, mRNA analysis was used to investigate the modulation of genes associated with skin regeneration. Subsequently, the regenerative potential of the peptides was further confirmed using an ex vivo organotypic model of human skin (hOSEC)-based lesion. Our results indicate that the three molecules evaluated in this study have regenerative potential at nontoxic doses (i.e., 200 µM for Clavanin-A and Clavanin-MO, and 6.25 µM for Mastoparan-MO). At these concentrations, all peptides promoted the proliferation and migration of hFibs during in vitro assays. Such processes were accompanied by gene expression signatures related to skin regenerative processes, including significantly higher KI67, HAS2 and CXCR4 mRNA levels induced by Clavanin A and Mastoparan-MO. Such findings translated into significantly accelerated wound healing promoted by both Clavanin A and Mastoparan-MO in hOSEC-based lesions. Overall, the data demonstrate the proregenerative properties of these peptides using human experimental skin models, with Mastoparan-MO and Clavanin A showing much greater potential for inducing wound healing compared to Clavanin-MO.
Assuntos
Movimento Celular , Proliferação de Células , Fibroblastos , Regeneração , Pele , Cicatrização , Humanos , Cicatrização/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regeneração/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos Antimicrobianos/farmacologia , Células Cultivadas , Peptídeos/farmacologiaRESUMO
Millions of people worldwide are affected by leishmaniasis, caused by the Leishmania parasite. Effective treatment is challenging due to the biological complexity of the parasite, drug toxicity, and increasing resistance to conventional drugs. To combat this disease, the development of specific strategies to target and selectively eliminate the parasite is crucial. This Review highlights the importance of amino acids in the developmental stages of Leishmania as a factor determining whether the infection progresses or is suppressed. It also explores the use of peptides as alternatives in parasite control and the development of novel targeted treatments. While these strategies show promise for more effective and targeted treatment, further studies to address the remaining challenges are imperative.
Assuntos
Aminoácidos , Antiprotozoários , Leishmania , Leishmaniose , Peptídeos , Leishmania/efeitos dos fármacos , Aminoácidos/química , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Humanos , Peptídeos/farmacologia , Peptídeos/química , Antiprotozoários/farmacologia , Antiprotozoários/química , AnimaisRESUMO
Cancer prevails as one of the major health concerns worldwide due to the consistent rise in incidence and lack of effective therapies. Previous studies identified the peptides KLKKNL, MLKSKR, and KKYRVF from Salvia hispanica seeds and stated their selective anticancer activity. Thus, this study aimed to determine the cell death pathway induced by these peptides on five cancer cell lines (MCF-7, Caco2, HepG2, DU145, and HeLa). Based on the results of this work, it is possible to suggest that KLKKNL primarily induces selective cancer cell death through the apoptotic pathway in the Caco2 and HeLa lines. On the other hand, the peptide KKYRVF reported the highest statistical (p < 0.05) selective cytotoxic effect on the MCF-7, Caco2, HepG2, and DU145 cancer cell lines by induction of the necrotic pathway. These findings offer some understanding of the selective anticancer effect of KLKKNL, MLKSKR, and KKYRVF.
Assuntos
Apoptose , Peptídeos , Salvia , Sementes , Humanos , Sementes/química , Peptídeos/farmacologia , Peptídeos/química , Apoptose/efeitos dos fármacos , Salvia/química , Linhagem Celular Tumoral , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proliferação de Células/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Plantas/farmacologia , Proteínas de Plantas/químicaRESUMO
BACKGROUND: Peptide drugs are advantageous because they are subject to rational design and exhibit highly diverse structures and broad biological activities. The NS2B-NS3 protein is a particularly promising flavivirus therapeutic target, with extensive research on the development of inhibitors as therapeutic candidates, and was used as a model in this work to determine the mechanism by which GA-Hecate inhibits ZIKV replication. OBJECTIVE: The present study aimed to evaluate the potential of GA-Hecate, a new antiviral developed by our group, against the Brazilian Zika virus and to evaluate the mechanism of action of this compound on the flavivirus NS2B-NS3 protein. METHODS: Solid-phase peptide Synthesis, High-Performance Liquid Chromatography, and Mass Spectrometry were used to obtain, purify, and characterize the synthesized compound. Real-time and enzymatic assays were used to determine the antiviral potential of GA-Hecate against ZIKV. RESULTS: The RT-qPCR results showed that GA-Hecate decreased the number of ZIKV RNA copies in the virucidal, pre-treatment, and post-entry assays, with 5- to 6-fold fewer RNA copies at the higher nontoxic concentration in Vero cells (HNTC: 10 µM) than in the control cells. Enzymatic and kinetic assays indicated that GA-Hecate acts as a competitive ZIKV NS2B-NS3 protease inhibitor with an IC50 of 32 nM and has activity against the yellow fever virus protease. CONCLUSION: The results highlight the antiviral potential of the GA-Hecate bioconjugate and open the door for the development of new antivirals.
Assuntos
Antivirais , Proteínas não Estruturais Virais , Replicação Viral , Zika virus , Zika virus/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Chlorocebus aethiops , Células Vero , Replicação Viral/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Peptídeos/farmacologia , Peptídeos/química , RNA Helicases/metabolismo , RNA Helicases/antagonistas & inibidores , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/virologia , Humanos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Proteases Virais , Nucleosídeo-Trifosfatase , RNA Helicases DEAD-boxRESUMO
With their diverse biological activities, peptides are promising candidates for therapeutic applications, showing antimicrobial, antitumour and hormonal signalling capabilities. Despite their advantages, therapeutic peptides face challenges such as short half-life, limited oral bioavailability and susceptibility to plasma degradation. The rise of computational tools and artificial intelligence (AI) in peptide research has spurred the development of advanced methodologies and databases that are pivotal in the exploration of these complex macromolecules. This perspective delves into integrating AI in peptide development, encompassing classifier methods, predictive systems and the avant-garde design facilitated by deep-generative models like generative adversarial networks and variational autoencoders. There are still challenges, such as the need for processing optimization and careful validation of predictive models. This work outlines traditional strategies for machine learning model construction and training techniques and proposes a comprehensive AI-assisted peptide design and validation pipeline. The evolving landscape of peptide design using AI is emphasized, showcasing the practicality of these methods in expediting the development and discovery of novel peptides within the context of peptide-based drug discovery.
Assuntos
Inteligência Artificial , Descoberta de Drogas , Peptídeos , Peptídeos/química , Peptídeos/uso terapêutico , Peptídeos/farmacologia , Descoberta de Drogas/métodos , Humanos , Desenho de Fármacos , Aprendizado de Máquina , Biologia Computacional/métodosRESUMO
Human alphaherpesvirus 1 (HSV-1) is a significantly widespread viral pathogen causing recurrent infections that are currently incurable despite available treatment protocols. Studies have highlighted the potential of antimicrobial peptides sourced from Vespula lewisii venom, particularly those belonging to the mastoparan family, as effective against HSV-1. This study aimed to demonstrate the antiviral properties of mastoparans, including mastoparan-L [I5, R8], mastoparan-MO, and [I5, R8] mastoparan, against HSV-1. Initially, Vero cell viability was assessed in the presence of these peptides, followed by the determination of antiviral activity, mechanism of action, and dose-response curves through plaque assays. Structural analyses via circular dichroism and nuclear magnetic resonance were conducted, along with evaluating membrane fluidity changes induced by [I5, R8] mastoparan using fluorescence-labeled lipid vesicles. Cytotoxic assays revealed high cell viability (>80%) at concentrations of 200 µg/mL for mastoparan-L and mastoparan-MO and 50 µg/mL for [I5, R8] mastoparan. Mastoparan-MO and [I5, R8] mastoparan exhibited over 80% HSV-1 inhibition, with up to 99% viral replication inhibition, particularly in the early infection stages. Structural analysis indicated an α-helical structure for [I5, R8] mastoparan, suggesting effective viral particle disruption before cell attachment. Mastoparans present promising prospects for HSV-1 infection control, although further investigation into their mechanisms is warranted.
Assuntos
Antivirais , Herpesvirus Humano 1 , Peptídeos e Proteínas de Sinalização Intercelular , Peptídeos , Venenos de Vespas , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Antivirais/farmacologia , Antivirais/química , Animais , Células Vero , Chlorocebus aethiops , Peptídeos/farmacologia , Peptídeos/química , Venenos de Vespas/farmacologia , Venenos de Vespas/química , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Sobrevivência Celular/efeitos dos fármacos , Humanos , Replicação Viral/efeitos dos fármacosRESUMO
The skin of fish is a physicochemical barrier that is characterized by being formed by cells that secrete molecules responsible for the first defense against pathogenic organisms. In this study, the biological activity of peptides from mucus of Seriola lalandi and Seriolella violacea were identified and characterized. To this purpose, peptide extraction was carried out from epidermal mucus samples of juveniles of both species, using chromatographic strategies for purification. Then, the peptide extracts were characterized to obtain the amino acid sequence by mass spectrometry. Using bioinformatics tools for predicting antimicrobial and antioxidant activity, 12 peptides were selected that were chemically produced by simultaneous synthesis using the Fmoc-Tbu strategy. The results revealed that the synthetic peptides presented a random coil or extended secondary structure. The analysis of antimicrobial activity allowed it to be discriminated that four peptides, named by their synthesis code 5065, 5069, 5070, and 5076, had the ability to inhibit the growth of Vibrio anguillarum and affected the copepodite stage of C. rogercresseyi. On the other hand, peptides 5066, 5067, 5070, and 5077 had the highest antioxidant capacity. Finally, peptides 5067, 5069, 5070, and 5076 were the most effective for inducing respiratory burst in fish leukocytes. The analysis of association between composition and biological function revealed that the antimicrobial activity depended on the presence of basic and aromatic amino acids, while the presence of cysteine residues increased the antioxidant activity of the peptides. Additionally, it was observed that those peptides that presented the highest antimicrobial capacity were those that also stimulated respiratory burst in leukocytes. This is the first work that demonstrates the presence of functional peptides in the epidermal mucus of Chilean marine fish, which provide different biological properties when the fish face opportunistic pathogens.