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PURPOSE: Sleep problems are a significant issue in patients with lung cancer, and resilience is a closely related factor. However, few studies have identified subgroups of resilience and their relationship with sleep quality. This study aimed to investigate whether there are different profiles of resilience in patients with lung cancer, to determine the sociodemographic characteristics of each subgroup, and to determine the relationship between resilience and sleep quality in different subgroups. METHODS: A total of 303 patients with lung cancer from four tertiary hospitals in China completed the General Sociodemographic sheet, the Connor-Davidson Resilience Scale, and the Pittsburgh Sleep Quality Index. Latent profile analysis was applied to explore the latent profiles of resilience. Multivariate logistic regression was used to analyze the sociodemographic variables in each profile, and ANOVA was used to explore the relationships between resilience profiles and sleep quality. RESULTS: The following three latent profiles were identified: the "high-resilience group" (30.2%), the "moderate-resilience group" (46.0%), and the "low-resilience group" (23.8%). Gender, place of residence, and average monthly household income significantly influenced the distribution of resilience in patients with lung cancer. CONCLUSION: The resilience patterns of patients with lung cancer varied. It is suggested that health care providers screen out various types of patients with multiple levels of resilience and pay more attention to female, rural, and poor patients. Additionally, individual differences in resilience may provide an actionable means for addressing sleep problems.
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Neoplasias Pulmonares , Testes Psicológicos , Resiliência Psicológica , Transtornos do Sono-Vigília , Humanos , Feminino , Qualidade do Sono , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologiaRESUMO
PURPOSE: This study aimed to investigate the performance, cost-effectiveness and additional findings of combined detailed ultrasound and biochemical screening for risks of major fetal trisomies in the first-trimester. METHODS: This is a retrospective analysis study, we estimated the risk of trisomies 21, 18 and 13 based on maternal age, fetal nuchal translucency thickness, nasal bone, ductus venosus pulsatility index velocity, tricuspid regurgitation, fetal heart rate, free beta-human chorionic gonadotropin, and pregnancy-associated plasma protein A in singleton pregnant women, and performed non-invasive prenatal testing for women with risks of trisomy 21 between 1:500 and 1:300. Invasive diagnostic testing was performed for women with positive or failed non-invasive prenatal testing result and in the high-risk group of this screening method. The direct costs were compared between this strategy and the non-invasive prenatal testing which alone used as first-line screening for all pregnant women. RESULTS: Among 25,155 singleton pregnant women who underwent screening, 24,361 were available for analysis, of these, 194 cases underwent non-invasive prenatal testing. Among the 24,361 women, 39, 19, and 7 had trisomies 21, 18 and 13, respectively. The use of this strategy could potentially detect approximately 94.87% of trisomy 21 cases, 100% of trisomy 18 cases, and 100% of trisomy 13 cases, with false-positive rates of 2.49%, 0.41%, and 0.49%, respectively. The overall detection rate and overall false-positive rates were 96.92% and 2.52%, respectively. The detection rate was 100% in the advanced age group and 94.12% in the general age group. Additionally, structural abnormalities were detected in 137 fetuses, and 44 fetuses had other chromosomal abnormalities. The total cost of this strategy was $3,730,843.30, and the cost per person tested was $153.15. The total cost of using non-invasive prenatal testing as the first-line strategy would be $6,813,387.04 and the cost per person tested was $279.68. CONCLUSIONS: Our strategy is an efficient and cost-effective approach for detecting major trisomies and identifying more fetuses with a potential abnormality. Therefore, this strategy is a valuable screening method and highly feasible in the clinical setting.
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BACKGROUND: Promoting self-directed learning (SDL) among nursing undergraduates is crucial to meet the new requirements of the healthcare system and to adapt to online learning contexts during the COVID-19 pandemic. Therefore, identifying the classification features of SDL ability and developing targeted interventions are both critical. Professional identity (PI) may contribute to the cultivation of SDL ability, but their relationship remains relatively unknown. This study aimed to explore the subgroups of SDL ability and their differences in PI among nursing undergraduates during the COVID-19 pandemic. METHODS: A total of 2438 nursing undergraduates at four universities in China were enrolled in this cross-sectional study from November 2021 to February 2022. The Self-Directed Learning Scale of Nursing Undergraduates (SLSNU) and the Professional Identity Scale for Nursing Students (PISNS) were administered. A latent profile analysis was performed to explore SDL ability latent profiles. Multinomial logistic regression analysis was conducted to examine the predictors of profile membership, and a one-way analysis of variance was applied to compare the PI scores in each latent profile. RESULTS: Three latent profiles were identified and labeled 'low SDL ability' (n = 749, 30.7%), 'low initiative of help-seeking' (n = 1325, 54.4%) and 'high SDL ability' (n = 364, 14.9%). Multinomial logistic regression analysis suggested that nursing undergraduates who voluntarily chose a nursing major, had served as a student cadre, and had participated in clinical practicum were less likely to be included in the "low SDL ability" group. The average PI score was statistically different across the three profiles (F = 884.40, p < 0.001). CONCLUSION: The SDL ability among nursing undergraduates was divided into three profiles, and results show that promoting PI may effectively foster SDL ability. This study highlights the importance of targeted interventions by considering their distinct SDL ability patterns, especially during the COVID-19 pandemic.
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The engineering of naturally occurring disulfide-rich peptides (DRPs) has been significantly hampered by the difficulty of manipulating disulfide pairing. New DRPs that take advantage of fold-directing motifs and noncanonical thiol-bearing amino acids are easy-to-fold with expected disulfide connectivities, representing a new class of scaffolds for the development of peptide ligands and therapeutics. However, the limited diversity of the scaffolds and particularly the use of noncanonical amino acids [e.g., penicillamine (Pen)] that are difficult to be translated by ribosomes greatly hamper the further development and application of these DRPs. Here, we designed and synthesized noncanonical bisthiol motifs bearing sterically obstructed thiol groups analogous to the Pen thiol to direct the folding of peptides into specific bicyclic and tricyclic structures. These bisthiol motifs can be ribosomally incorporated into peptides through a commercially available PURE system integrated with genetic code reprograming, which enables, for the first time, the in vitro expression of bicyclic peptides with two noncanonical and orthogonal disulfide bonds. We further constructed a bicyclic peptide library encoded by mRNA, with which new bicyclic peptide ligands with nanomolar affinity to proteins were successfully selected. Therefore, this study provides a new, general, and robust method for discovering de novo DRPs with new structures and functions not derived from natural peptides, which would greatly benefit the field of peptide drug discovery.
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Dissulfetos , Biblioteca de Peptídeos , Aminoácidos , Dissulfetos/química , Ligantes , Peptídeos/química , Ribossomos , Compostos de SulfidrilaRESUMO
Oxidative lesions, such as 8-oxo-dG and 8-oxo-dA, are continuously generated from exposure to reactive oxygen species. While 8-oxo-dG has been extensively studied, 8-oxo-dA has not received as much attention until recently. Herein, we report the synthesis of duplex DNAs incorporating dA, 8-oxo-dA, 7-deaza-dA, 8-Br-dA, and 8-Br-7-deaza-dA, which have different substitutions at 7- and 8-position, for the investigation into the implications of N7-hydrogen and C8-keto on the base pairing preference, mutagenic potential and repair of 8-oxo-dA. Base pairing study suggested that the polar N7-hydrogen and C8-keto of 8-oxo-dA, rather than the syn-preference, might be essential for 8-oxo-dA to form a stable base pair with dG. Insertion and extension studies using KF-exo- and human DNA polymerase ß indicated that the efficient dGTP insertion opposite 8-oxo-dA and extension past 8-oxo-dA:dG are contingent upon not only the stable base pair with dG, but also the flexibility of the active site in polymerase. The N7-hydrogen in 8-oxo-dA or C7-hydrogen in 7-deaza-dA and 8-Br-7-deaza-dA was suggested to be important for the recognition by hOGG1, although the excision efficiencies of 7-deaza-dA and 8-Br-7-deaza-dA were much lower than 8-oxo-dA. This study provides an insight into the structure-function relationship of 8-oxo-dA by nucleotide analogues.
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Desoxiguanosina , Mutagênicos , 8-Hidroxi-2'-Desoxiguanosina , Adenosina , Pareamento de Bases , Desoxiguanosina/química , Humanos , Hidrogênio , Mutagênicos/químicaRESUMO
AIM: The aim was to examine the subgroups of work engagement in frontline nurses during the COVID-19 pandemic. BACKGROUND: The pandemic may affect the work engagement of nurses who have direct contact with infected patients and lead to a poor quality of care. Identifying classification features of work engagement and tailoring interventions to support frontline nurses is imperative. DESIGN: This study utilized a cross-sectional study design. METHODS: Three hundred fifty-five nurses were enrolled in this cross-sectional study from 14 February to 15 April 2020. A latent profile analysis was performed to identify classification features of work engagement. Multiple logistic regression analyses were used to examine predictors of profile membership. RESULTS: A four-profile model provided the best fit. The four profiles were titled 'low work engagement' (n = 99), 'high vigour-low dedication and absorption' (n = 58), 'moderate work engagement' (n = 63) and 'high work engagement' (n = 135). A regression analysis suggested that young nurses and nurses who were the only children of their family were more likely to be in the 'low work engagement' and 'high vigour-low dedication and absorption' groups. CONCLUSION: This study highlights the importance of tailoring interventions for frontline supporting nurses by considering their distinct work engagement patterns, especially during the COVID-19 pandemic, to improve the promotion of work satisfaction and quality of care. IMPACT: This was the first study to explore the latent profiles of work engagement in frontline nurses during the COVID-19 pandemic. Over 40% of nurses were in the 'low work engagement' and 'high vigour-low dedication and absorption' groups and reported low levels of work engagement. Understanding different patterns of work engagement in frontline nurses can help nursing managers provide emotional, material and organizational support based on the features of each latent profile, which may improve the quality of care and patient safety.
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COVID-19 , Enfermeiras e Enfermeiros , Criança , Humanos , Engajamento no Trabalho , COVID-19/epidemiologia , Pandemias , Estudos Transversais , Satisfação no EmpregoRESUMO
This integrative review aims to explore the current state of dyadic interventions in older people with chronic diseases and to review how these interventions are developed and conducted. 'Older people' and 'dyadic intervention' were searched in six databases to include studies published before August 2021. The constant comparison method was used for data synthesis, combined with the Joanna Briggs Institute (JBI)1 and mixed methods appraisal tool (MMAT)2 to assess the quality of the literature. Nineteen studies were included and could be divided into four types in which caregivers could be seen as subordinators, directors, cooperators and collaborators. Dyadic interaction could be observed in all studies, including dyad coled, patient-led, and caregiver-led interactions. The outcome indicators included patient-, caregiver-, dyad-, and family-related indicators. It is important not only to include the dyad but also to consider the dyadic interactions. In the future, dyadic intervention can be guided by matching dyadic theories. NO PATIENT OR PUBLIC CONTRIBUTION: This study is an integrative review; the study population was not directly contacted. Data from included studies were analysed and interpreted.
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Cuidadores , Relações Interpessoais , Humanos , Idoso , Doença CrônicaRESUMO
d/l-Hybrid peptides are an attractive class of molecular modality because they are able to exhibit high proteolytic stability and unique structural diversity which cannot be accessed by those consisting of only proteinogenic l-amino acids. Despite such an expectation, it has not been possible to devise de novo d/l-hybrid peptides capable of disrupting the function of a protein target(s) due to the lack of an effective method that reliably constructs a highly diverse library and screens active species. Here we report for the first time construction of a library consisting of 1012 members of macrocyclic d/l-hybrid peptides containing five kinds of d-amino acids and performance of the RaPID selection against human EGFR as a showcase to uncover PPI (protein-protein interaction) inhibitors.
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Aminoácidos/química , Peptídeos Cíclicos/metabolismo , Sequência de Aminoácidos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Meia-Vida , Humanos , Cinética , Peptídeos Cíclicos/sangue , Peptídeos Cíclicos/química , Ligação Proteica , Mapas de Interação de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estabilidade ProteicaRESUMO
Peptides inherently feature the favorable properties of being easily synthesized, water-soluble, biocompatible, and typically non-toxic. Thus, boronic acid has been widely integrated with peptides with the goal of discovering peptide ligands with novel biological activities, and this effort has led to broad applications. Taking the integration between boronic acid and peptide as a starting point, we provide an overview of the latest research advances and highlight the versatile and robust functionalities of boronic acid. In this review, we summarize the diverse applications of peptide boronic acids in medicinal chemistry and chemical biology, including the identification of covalent reversible enzyme inhibitors, recognition, and detection of glycans on proteins or cancer cell surface, delivery of siRNAs, development of pH responsive devices, and recognition of RNA or bacterial surfaces. Additionally, we discuss boronic acid-mediated peptide cyclization and peptide modifications, as well as the facile chemical synthesis of peptide boronic acids, which paved the way for developing a growing number of peptide boronic acids.
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Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Ácidos Borônicos/síntese química , Bortezomib/química , Bortezomib/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicina/análogos & derivados , Glicina/química , Glicina/farmacologia , Humanos , Peptídeos/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologiaRESUMO
Peptides as a therapeutic modality attract much attention due to their synthetic accessibility, high degree of specific binding, and the ability to target protein surfaces traditionally considered "undruggable". Unfortunately, at the same time, other pharmacological properties of a generic peptide, such as metabolic stability and cell permeability, are quite poor, which limits the success of de novo discovered biologically active peptides as drug candidates. Here, we review how macrocyclization as well as the incorporation of nonproteogenic amino acids and various conjugation strategies may be utilized to improve on these characteristics to create better drug candidates. We analyze recent progress and remaining challenges in improving individual pharmacological properties of bioactive peptides, and offer our opinion on interfacing these, often conflicting, considerations, to create balanced drug candidates as a potential way to make further progress in this area.
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Descoberta de Drogas , Peptídeos Cíclicos/metabolismo , Animais , Permeabilidade da Membrana Celular , Ciclização , Humanos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacocinética , Estabilidade ProteicaRESUMO
l-Carboranylalanine (LCba) is a unique artificial amino acid containing a cluster of 10 boron atoms. Since the three-dimensional aromaticity and charge distributions of the carborane side chain are quite different from any side chains of proteinogenic amino acids, there is no report whether LCba can be a substrate for the translation machinery. Here, we report studies on the ribosomal incorporation of LCba into peptide via initiation and elongation using the flexizyme-assisted translation system. Our results indicate that only the initiation step could tolerate LCba incorporation, but the elongation steps could not, very likely due to its steric bulkiness of the side chain. Based on this knowledge, we have designed a library of macrocyclic peptides initiated by α-N-(2-choloroacetyl)-l-carboranylalanine (ClAc-LCba) and selected molecules capable of binding to human epidermal growth factor receptor (hEGFR). Two peptides that were forwarded to deeper studies exhibited affinities with KD values at 16 and 20 nM against hEGFR. Computational modeling of one of the peptides suggested that the carborane side chain might be directly involved in the interaction with the hydrophobic ß-sheet core in the EGF binding site of hEGFR, which is consistent with the mutational data where replacing LCba residue with LPhe completely eliminated the binding activity. Cell lines that stably express hEGFR could be stained by incubation with the C-terminal fluorescein-labeled peptides, whereas hEGFR-negative cells could not be stained. This study provides a general strategy for the de novo discovery of carborane-containing macrocyclic peptides targeting various tumor biomarker proteins, potentially applicable to boron neutron capture therapy.
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Compostos de Boro/química , Compostos Macrocíclicos/síntese química , Peptídeos Cíclicos/síntese química , Fenilalanina/análogos & derivados , Sítios de Ligação , Terapia por Captura de Nêutron de Boro , Receptores ErbB/química , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Simulação de Acoplamento Molecular , Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Fenilalanina/química , Ligação Proteica , Técnicas de Síntese em Fase SólidaRESUMO
This quasi-experimental study aimed to evaluate the positive psychological intervention of recording three good things on alleviating nurses' burnout. Eighty-seven nurses with burnout were recruited. Nurses in the study group recorded three good things using communication tool WeChat for six months, no records were made in the control group. After intervention, the score of exhaustion decreased considerably for nurses in the study group. Nurses recording three good things on average twice a week returned the lowest score of exhaustion. This intervention combined with appropriate surveillance and encouragement is recommended to reduce nurses' burnout and create a positive work environment.
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Esgotamento Profissional/prevenção & controle , Enfermeiras e Enfermeiros/psicologia , Adulto , Feminino , Humanos , Masculino , Enfermeiras e Enfermeiros/estatística & dados numéricos , Escalas de Graduação Psiquiátrica , Local de Trabalho/psicologia , Adulto JovemRESUMO
Bicyclic and tricyclic peptides have emerged as promising candidates for the development of protein binders and new therapeutics. However, convenient and efficient strategies that can generate topologically controlled bicyclic and tricyclic peptide scaffolds from fully-unprotected peptides are still much in demand, particularly for those amenable to the design of biosynthetic libraries. In this work, we report a reliable chemical and ribosomal synthesis of topologically controlled bicyclic and tricyclic peptide scaffolds. Our strategy involves the combination of selenoether cyclization followed by disulfide or thioether cyclization, yielding desirable bicyclic and tricyclic peptides. This work thus lays the foundation for developing peptide libraries with controlled topology of multicyclic scaffolds for inâ vitro display techniques.
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Peptídeos/síntese química , Ribossomos/química , Estrutura Molecular , Peptídeos/químicaRESUMO
hMTH1 (8-oxo-2'-deoxyguanine triphosphatase) hydrolyzes oxidized nucleoside triphosphates; its presence is non-essential for survival of normal cells but is required for survival of cancer cells. In this study, 8-halogenated-7-deaza-2'-deoxyguanosine triphosphate (8-halogenated-7-deazadGTP) derivatives were synthesized. Interestingly, these triphosphates were poor substrates for hMTH1, but exhibited strong competitive inhibition against hMTH1 at nanomolar levels. This inhibitory effect is attributed to slower rate of hydrolysis, possibly arising from enzyme structural changes, specifically different stacking interactions with 8-halogenated-7-deazadGTP. This is the first example of using nucleotide derivatives to inhibit hMTH1, thus demonstrating their potential as antitumor agents.
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Enzimas Reparadoras do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/metabolismo , Nucleotídeos de Desoxiguanina/farmacologia , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cromatografia Líquida de Alta Pressão , Nucleotídeos de Desoxiguanina/síntese química , Nucleotídeos de Desoxiguanina/química , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Halogênios/síntese química , Halogênios/química , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Estrutura MolecularRESUMO
8-OxodG (8-oxo-2'-deoxyguanosine) is representative of nucleoside damage and shows a genotoxicity. To significantly reveal the contributions of 7-NH and C8-oxygen to the mutagenic effect of 8-oxodG by DNA polymerases, we evaluated the effects of the 8-halo-7-deaza-dG (8-halogenated 7-deaza-2'-deoxyguanosine) derivatives by DNA polymerases. 8-Halo-7-deaza-dGTPs were poorly incorporated by both KF(exo(-)) and human DNA polymerase ß opposite dC or dA into the template DNA. Furthermore, it was found that KF(exo(-)) was very sensitive to the introduction of the C8-halogen, while polymerase ß can accommodate the C8-halogen resulting in an efficient dCTP insertion opposite the 8-halo-7-deaza-dG in the template DNA. These results indicate that strong hydrogen bonding between 7-NH in the 8-oxo-G nucleobase and 1-N in the adenine at the active site of the DNA polymerase is required for the mutagenic effects. Whereas, I-deaza-dGTP shows an antiproliferative effect for the HeLa cells, suggesting that it could become a candidate as a new antitumor agent.
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Proliferação de Células/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/metabolismo , Nucleotídeos de Desoxiguanina/química , Nucleotídeos de Desoxiguanina/farmacologia , Humanos , Ligação de HidrogênioRESUMO
Cellular DNA continuously suffers various types of damage, and unrepaired damage increases disease progression risk. 8-Oxo-2'-deoxyguanine (8-oxo-dG) is excised by repair enzymes, and their analogues are of interest as inhibitors and as bioprobes for study of these enzymes. We have developed 8-halogenated-7-deaza-2'-deoxyguanosine derivatives that resemble 8-oxo-dG in that they adopt the syn conformation. In this study, we investigated their effects on Fpg (formamidopyrimidine DNA glycosylase) and hOGG1 (human 8-oxoguanine DNA N-glycosylase 1). Relative to 8-oxo-dG, Cl- and Br-deaza-dG were good substrates for Fpg, whereas they were less efficient substrates for hOGG1. Kinetics and binding experiments indicated that, although hOGG1 effectively binds Cl- and Br-deaza-dG analogues with low Km values, their lower kcat values result in low glycosylase activities. The benefits of the high binding affinities and low reactivities of 8-oxo-dG analogues with hOGG1 have been successfully applied to the competitive inhibition of the excision of 8-oxoguanine from duplex DNA by hOGG1.
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DNA Glicosilases/antagonistas & inibidores , DNA-Formamidopirimidina Glicosilase/antagonistas & inibidores , DNA/metabolismo , Desoxiguanosina/análogos & derivados , Halogenação , 8-Hidroxi-2'-Desoxiguanosina , Sequência de Bases , DNA/química , DNA/genética , DNA Glicosilases/química , DNA Glicosilases/metabolismo , Reparo do DNA/efeitos dos fármacos , DNA-Formamidopirimidina Glicosilase/química , DNA-Formamidopirimidina Glicosilase/metabolismo , Desoxiguanosina/química , Desoxiguanosina/metabolismo , Desoxiguanosina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Cinética , Modelos Moleculares , Conformação ProteicaRESUMO
BACKGROUND: Although the number of studies focusing on life satisfaction in women with cervical cancer is increasing, there are limited studies on the pathway between social support and life satisfaction in this population. OBJECTIVE: This study explored the pathway between social support and life satisfaction in women with cervical cancer by examining the serial mediating effects of self-care self-efficacy, coping strategies, and depressive symptoms. METHODS: In this cross-sectional study, a total of 292 women with cervical cancer completed a questionnaire for assessing social support, self-efficacy, coping strategies, depressive symptoms, and life satisfaction. Structural equation modeling was used to test the direct and/or indirect effects of the variables on life satisfaction. RESULTS: Structural equation modeling analysis indicated that self-efficacy, coping strategies, and depressive symptoms mediates the effect of social support on life satisfaction. Direct paths from social support to life satisfaction, social support to self-efficacy, self-efficacy to coping strategies, coping strategies to depressive symptoms, and depressive symptoms to life satisfaction were significant ( P < .05). Moreover, indirect paths from social support to life satisfaction, self-efficacy to life satisfaction, and coping strategies to life satisfaction were also significant ( P < .05). CONCLUSIONS: Self-care self-efficacy, coping strategies, and depressive symptoms are potential pathways through which social support may affect life satisfaction in women with cervical cancer. IMPLICATION: Healthcare providers, family, and friends should offer more social support to the patients and make efforts to strengthen their self-care self-efficacy, facilitate active coping, and alleviate depressive symptoms to improve women's life satisfaction.
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Neoplasias do Colo do Útero , Humanos , Feminino , Estudos Transversais , Apoio Social , Adaptação Psicológica , Satisfação Pessoal , DepressãoRESUMO
Macrocyclic peptides possess unique features, making them highly promising as a drug modality. However, evaluating their bioactivity through wet lab experiments is generally resource-intensive and time-consuming. Despite advancements in artificial intelligence (AI) for bioactivity prediction, challenges remain due to limited data availability and the interpretability issues in deep learning models, often leading to less-than-ideal predictions. To address these challenges, we developed PepExplainer, an explainable graph neural network based on substructure mask explanation (SME). This model excels at deciphering amino acid substructures, translating macrocyclic peptides into detailed molecular graphs at the atomic level, and efficiently handling non-canonical amino acids and complex macrocyclic peptide structures. PepExplainer's effectiveness is enhanced by utilizing the correlation between peptide enrichment data from selection-based focused library and bioactivity data, and employing transfer learning to improve bioactivity predictions of macrocyclic peptides against IL-17C/IL-17 RE interaction. Additionally, PepExplainer underwent further validation for bioactivity prediction using an additional set of thirteen newly synthesized macrocyclic peptides. Moreover, it enabled the optimization of the IC50 of a macrocyclic peptide, reducing it from 15 nM to 5.6 nM based on the contribution score provided by PepExplainer. This achievement underscores PepExplainer's skill in deciphering complex molecular patterns, highlighting its potential to accelerate the discovery and optimization of macrocyclic peptides.
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Aprendizado Profundo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Estrutura Molecular , Humanos , Peptídeos/química , Peptídeos/farmacologia , Relação Estrutura-Atividade , Relação Dose-Resposta a DrogaRESUMO
Peptide-bile acid hybrids offer promising drug candidates due to enhanced pharmacological properties, such as improved protease resistance and oral bioavailability. However, it remains unknown whether bile acids can be incorporated into peptide chains by the ribosome to produce a peptide-bile acid hybrid macrocyclic peptide library for target-based de novo screening. In this study, we achieved the ribosomal incorporation of lithocholic acid (LCA)-d-tyrosine into peptide chains. This led to the construction of a peptide-LCA hybrid macrocyclic peptide library, which enabled the identification of peptides TP-2C-4L3 (targeting Trop2) and EP-2C-4L5 (targeting EphA2) with strong binding affinities. Notably, LCA was found to directly participate in binding to EphA2 and confer on the peptides improved stability and resistance to proteases. Cell staining experiments confirmed the high specificity of the peptides for targeting Trop2 and EphA2. This study highlights the benefits of LCA in peptides and paves the way for de novo discovery of stable peptide-LCA hybrid drugs.
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Ácido Litocólico , Biblioteca de Peptídeos , Peptídeos , Ribossomos , Ácido Litocólico/química , Ácido Litocólico/análogos & derivados , Ácido Litocólico/metabolismo , Ribossomos/metabolismo , Humanos , Peptídeos/química , Peptídeos/metabolismo , Receptor EphA2/metabolismo , Receptor EphA2/química , Descoberta de Drogas , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismoRESUMO
Fluorination has emerged as a promising strategy in medicinal chemistry to improve the pharmacological profiles of drug candidates. Similarly, incorporating fluorinated non-canonical amino acids into macrocyclic peptides expands chemical diversity and enhances their pharmacological properties, from improved metabolic stability to enhanced cell permeability and target interactions. However, only a limited number of fluorinated non-canonical amino acids, which are canonical amino acid analogs, have been incorporated into macrocyclic peptides by ribosomes for de novo construction and target-based screening of fluorinated macrocyclic peptides. In this study, we report the ribosomal translation of a series of distinct fluorinated non-canonical amino acids, including mono-to tri-fluorinated variants, as well as fluorinated l-amino acids, d-amino acids, ß-amino acids, etc. This enabled the de novo discovery of fluorinated macrocyclic peptides with high affinity for EphA2, and particularly the identification of those exhibiting broad-spectrum activity against Gram-negative bacteria by targeting the BAM complex. This study not only expands the scope of ribosomally translatable fluorinated amino acids but also underscores the versatility of fluorinated macrocyclic peptides as potent therapeutic agents.