Amino Acids最新文献

{"title":"Impact of smokeless tobacco on psychological and oxidative stress in unemployed indian youth","authors":"Anurag Mishra,&nbsp;Rishabh Kumar,&nbsp;Satya Narayan Mishra,&nbsp;Sivakumar Vijayaraghavalu,&nbsp;Girish C. Shukla,&nbsp;Munish Kumar","doi":"10.1007/s00726-024-03416-3","DOIUrl":"10.1007/s00726-024-03416-3","url":null,"abstract":"<div><p>In India, tobacco (nicotine) addiction among youth has increased, leading to substantial socioeconomic burdens, mortality, and morbidity. While minimal short-term nicotine consumption may have antioxidant effects, chronic exposure results in various adverse health outcomes. This study examines the impact of chronic nicotine consumption on cellular oxidative stress and psychological stress, and their correlation with Homocysteine (Hcy) levels in unemployed tobacco consumers. This case-control study included 156 healthy, educated, unemployed male volunteers aged 20–40 years, divided into nicotine-addicted (n = 80) and non-addicted (n = 76) groups. Psychological stress was assessed using perceived stress scales (PSS) and coping self-efficacy (CSE) scales. Oxidative stress markers, including Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Catalase, were measured. Hcy levels were quantified using high-performance liquid chromatography (HPLC). Nicotine-addicted participants exhibited significantly higher perceived stress (p = 0.0001) and lower coping self-efficacy (p = 0.0001) compared to non-addicted individuals. MDA levels in erythrocytes were significantly increased (p = 0.0006), while SOD (p = 0.0001) and Catalase (p = 0.02) activities were significantly decreased in the addicted group. Nicotine intake influenced Hcy concentrations, with 55% of addicted individuals falling into moderate, 27.5% into intermediate, and 7.5% into severe Hcy categories. Chronic nicotine intake also reflected the hematological parameters (WBCs, RBCs, HGB, and Platelets). Chronic tobacco consumption induces oxidative stress and perceived psychological stress, leading to elevated Hcy levels in nicotine consumers. The study highlights the detrimental effects of nicotine addiction on cellular defensive mechanisms, emphasizing the need for targeted interventions to address this growing health issue among unemployed Indian youth.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03416-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HECTD2 as a target for veratric acid in the regulation of ferroptosis in renal cell carcinoma","authors":"Dong Lv,&nbsp;Ying Xiang,&nbsp;Tao Song,&nbsp;Jinze Li,&nbsp;Yongbo Chen,&nbsp;Youlong Huili,&nbsp;Taimin Shen","doi":"10.1007/s00726-024-03419-0","DOIUrl":"10.1007/s00726-024-03419-0","url":null,"abstract":"<div><p>Function of HECTD2 in renal cell carcinoma malignant progression is undefined. Molecular mechanism behind anti-cancer effects of veratric acid (VA) from traditional Chinese medicine (TCM) is underexplored. The Cancer Genome Atlas was leveraged to study HECTD2 expression in renal cell carcinoma and its relationship with histological grading. Kaplan–Meier survival analysis was performed. HECTD2 expression was detected in cancer cells and tissues via qRT-PCR and immunohistochemistry. GPX4 and SLC7A11 expression in tumor samples with high or low HECTD2 expression was examined by immunohistochemistry, cell viability by CCK8, cell proliferation by colony formation assay, lipid ROS and mitochondrial superoxide levels by flow cytometry, Fe²⁺ and MDA content by assay kits, and GPX4 and SLC7A11 proteins by western blot. SeeSAR software screened TCM small molecule compounds with highest affinity to HECTD2, confirmed with cellular thermal shift assay. VA IC₅₀ was measured by CCK8. Xenograft model was developed and treated with VA. Tumor size and weight were monitored, with immunohistochemistry to detect HECTD2 expression in tumors and assess ferroptosis-related markers. HECTD2 was overexpressed in tumor tissues and cells, which positively correlated with histological grading. HECTD2 depletion inhibited cell vitality and proliferation, raised intracellular lipid ROS, mitochondrial superoxide, Fe²⁺, and MDA. HECTD2 was a target with highest VA affinity. In vitro and <i>vivo</i> experiments concurred that VA treatment hindered malignancy of renal cell carcinoma and enhanced its susceptibility to ferroptosis. HECTD2 supports ferroptosis resistance in renal cell carcinoma, but VA, through its targeting of HECTD2, initiates ferroptosis, showcasing its anti-cancer efficacy.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of amino acids metabolomic profiling in human plasma distinguishes lupus nephritis from systemic lupus erythematosus","authors":"Zui-Shuang Guo,&nbsp;Man-man Lu,&nbsp;Dong-wei Liu,&nbsp;Chun-Yu Zhou,&nbsp;Zhang-suo Liu,&nbsp;Qing Zhang","doi":"10.1007/s00726-024-03418-1","DOIUrl":"10.1007/s00726-024-03418-1","url":null,"abstract":"<div><p>Lupus nephritis (LN) is an immunoinflammatory glomerulonephritis associated with renal involvement in systemic lupus erythematosus (SLE). Given the close relationship between plasma amino acids (AAs) and renal function, this study aimed to elucidate the plasma AA profiles in LN patients and identify key AAs and diagnostic patterns that distinguish LN patients from those with SLE and healthy controls. Participants were categorized into three groups: normal controls (NC), SLE, and LN. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to quantify AA levels in human plasma. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to identify key AAs. The diagnostic capacity of the models was assessed using receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) values. Significant alterations in plasma AA profiles were observed in LN patients compared to the SLE and NC groups. The OPLS-DA model effectively separated LN patients from the SLE and NC groups. A joint model using histidine (His), lysine (Lys), and tryptophan (Trp) demonstrated exceptional diagnostic performance, achieving an AUC of 1.0 with 100% sensitivity, specificity, and accuracy in predicting LN. Another joint model comprising arginine (Arg), valine (Val), and Trp also exhibited robust predictive performance, with an AUC of 0.998, sensitivity of 93.80%, specificity of 100%, and accuracy of 95.78% in distinguishing between SLE and LN. The joint forecasting models showed excellent predictive capabilities in identifying LN and categorizing lupus disease status. This approach provides a novel perspective for the early identification, prevention, treatment, and management of LN based on variations in plasma AA levels.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-024-03418-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of supplementary carnosine accumulation and distribution: an initial analysis of participants in the Nucleophilic Defense Against PM Toxicity (NEAT) clinical trial","authors":"Shahid P. Baba,&nbsp;Alok R. Amraotkar,&nbsp;David Hoetker,&nbsp;Hong Gao,&nbsp;Daniel Gomes,&nbsp;Jingjing Zhao,&nbsp;Michael F. Wempe,&nbsp;Peter J. Rice,&nbsp;Andrew P. DeFilippis,&nbsp;Shesh N. Rai,&nbsp;C. Arden Pope III,&nbsp;Aruni Bhatnagar,&nbsp;Timothy E. O’Toole","doi":"10.1007/s00726-024-03414-5","DOIUrl":"10.1007/s00726-024-03414-5","url":null,"abstract":"<div><p>Carnosine is an endogenous dipeptide that buffers intracellular pH and quenches toxic products of lipid peroxidation. Used as a dietary supplement, it also supports exercise endurance. However, the accumulation and distribution of carnosine after supplementation has not been rigorously evaluated. To do this, we randomized a cohort to receive daily supplements of either placebo or carnosine (2 g/day). Blood and urine samples were collected twice over the subsequent 12 week supplementation period and we measured levels of red blood cell (RBC) carnosine, urinary carnosine, and urinary carnosine-propanol and carnosine-propanal conjugates by LC/MS–MS. We found that, when compared with placebo, supplementation with carnosine for 6 or 12 weeks led to an approximate twofold increase in RBC carnosine, while levels of urinary carnosine increased nearly sevenfold. Although there were no changes in the urinary levels of carnosine propanol, carnosine propanal increased nearly twofold. RBC carnosine levels were positively associated with urinary carnosine and carnosine propanal levels. No adverse reactions were reported by those in the carnosine or placebo arms, nor did carnosine supplementation have any effect on kidney, liver, and cardiac function or blood electrolytes. In conclusion<i>,</i> irrespective of age, sex, or BMI, oral carnosine supplementation in humans leads to its increase in RBC and urine, as well as an increase in urinary carnosine-propanal. RBC carnosine may be a readily accessible pool to estimate carnosine levels. <b>Clinical trial registration:</b> This study is registered with ClinicalTrials.gov (Nucleophilic Defense Against PM Toxicity (NEAT Trial)—Full Text View—ClinicalTrials.gov), under the registration: NCT03314987.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of weight loss interventions on metabolomic signatures in obese children with insulin resistance","authors":"Xiaoguang Liu,&nbsp;Lin Zhu,&nbsp;Jingxin Liu,&nbsp;Zichen Nie,&nbsp;Wenjun Qiu","doi":"10.1007/s00726-024-03409-2","DOIUrl":"10.1007/s00726-024-03409-2","url":null,"abstract":"<div><p>The obesity epidemic among children has become a major public health issue, and the presence of childhood insulin resistance (IR) has been demonstrated prior to the onset of type 2 diabetes mellitus. However, it is unclear whether the metabolomic signature is associated with weight loss interventions in obese children with IR. Thirty-six obese children with IR were selected from the weight loss camp (Shenzhen Sunshine Xing Yada health Technology Co., LTD). Clinical parameters were collected before and after weight loss intervention. Targeted metabolomics of plasma samples was performed by ultra-performance liquid chromatography coupled to the tandem mass spectrometry, and principal component analysis, variable importance in projection, and orthogonal partial least squares discriminant analysis were used to obtain the differentially expressed metabolites. Pathway analysis was conducted with the Homo sapiens (HSA) sets in the Kyoto Encyclopedia of Genes and Genomes. We used machine learning algorithms to obtain the potential biomarkers and Spearman correlation analysis to clarify the association between potential biomarkers and clinical parameters. We found that clinical parameters and metabolite clusters were significantly changed in obese children with IR before and after weight loss intervention. Mechanistically, weight loss intervention significantly changed 61 metabolites in obese children with IR. Furthermore, 12 pathways were significantly changed. Moreover, the machine learning algorithm found 6 important potential biomarkers. In addition, these potential biomarkers were strongly associated with major clinical parameters. These data indicate different metabolomic profiles in obese children with IR after weight loss intervention, providing insights into the clinical parameters and metabolite mechanisms involved in weight loss programs.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the interplay between kidney function and urinary metabolites in young adults: the African-PREDICT study","authors":"Wessel L. du Toit,&nbsp;Ruan Kruger,&nbsp;Lebo F. Gafane-Matemane,&nbsp;Aletta E. Schutte,&nbsp;Roan Louw,&nbsp;Catharina M. C. Mels","doi":"10.1007/s00726-024-03412-7","DOIUrl":"10.1007/s00726-024-03412-7","url":null,"abstract":"<div><p>The exposure to modifiable risk factors at young ages have been linked to premature fatal and non-fatal cardiovascular and kidney outcomes. The use of urinary metabolomics has shown strong predictability of kidney function and cardiovascular disease (CVD). We therefore determined the associations between estimated glomerular filtration rate (eGFR) and urinary metabolites in young adults with and without CVD risk factors. Apparently healthy Black and White sexes were included (aged 20–30 years) and categorised by the presence or absence of risk factors, i.e., obesity, physical inactivity, smoking, excessive alcohol intake, masked hypertension, hyperglycemia, dyslipidemia and low socio-economic status, forming the CVD risk group (N = 1036), CVD risk clusters (i.e. presenting with 1 CVD risk factor (N = 344), 2 CVD risk factors (N = 360) and 3 + CVD risk factors (N = 332)) and the control group (N = 166). eGFR was calculated with CKD-EPI equations. A targeted metabolomics approach using liquid chromatography-tandem mass spectrometry was used to measure amino acids and acylcarnitines. Lower cystatin C-based eGFR were indicated in the CVD risk group, 2 and 3 + CVD risk clusters compared to the control group (all P ≤ 0.033). In the CVD risk group, eGFR associated positively with histidine, lysine, asparagine, glycine, serine, glutamine, dimethylglycine, threonine, alanine, creatine, cystine, methionine, tyrosine, pyroglutamic acid, leucine/isoleucine, aspartic acid, tryptophan, glutamic acid, free carnitine, acetylcarnitine, propionylcarnitine, isovalerylcarnitine, octanoylcarnitine and decanoylcarnitine (all P ≤ 0.044), with similar results found in the CVD risk clusters, particularly the 2 CVD risk cluster. eGFR was positively associated with metabolites linked to aromatic amino acid and branched-chain amino acid metabolism, energy metabolism and oxidative stress. These findings may indicate altered reabsorption of these metabolites or altered metabolic regulation to preserve renal health in the setting of CVD risk factors at this young age without established CVD.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-carboxyacyl and N-α-aminoacyl derivatives of aminoaldehydes as shared substrates of plant aldehyde dehydrogenases 10 and 7","authors":"Michaela Masopustová,&nbsp;Adam Goga,&nbsp;Miroslav Soural,&nbsp;Martina Kopečná,&nbsp;Marek Šebela","doi":"10.1007/s00726-024-03415-4","DOIUrl":"10.1007/s00726-024-03415-4","url":null,"abstract":"<div><p>Aldehyde dehydrogenases (ALDHs) represent a superfamily of enzymes, which oxidize aldehydes to the corresponding acids. Certain families, namely ALDH9 and ALDH10, are best active with ω-aminoaldehydes arising from the metabolism of polyamines such as 3-aminopropionaldehyde and 4-aminobutyraldehyde. Plant ALDH10s show broad specificity and accept many different aldehydes (aliphatic, aromatic and heterocyclic) as substrates. This work involved the above-mentioned aminoaldehydes acylated with dicarboxylic acids, phenylalanine, and tyrosine. The resulting products were then examined with native ALDH10 from pea and recombinant ALDH7s from pea and maize. This investigation aimed to find a common efficient substrate for the two plant ALDH families. One of the best natural substrates of ALDH7s is aminoadipic semialdehyde carrying a carboxylic group opposite the aldehyde group. The substrate properties of the new compounds were demonstrated by mass spectrometry of the reaction mixtures, spectrophotometric assays and molecular docking. The <i>N</i>-carboxyacyl derivatives were good substrates of pea ALDH10 but were only weakly oxidized by the two plant ALDH7s. The <i>N</i>-phenylalanyl and <i>N</i>-tyrosyl derivatives of 3-aminopropionaldehyde were good substrates of pea and maize ALDH7. Particularly the former compound was converted very efficiently (based on the <i>k</i>_cat/<i>K</i>_m ratio), but it was only weakly oxidized by pea ALDH10. Although no compound exhibited the same level of substrate properties for both ALDH families, we show that these enzymes may possess more common substrates than expected.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11362210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Branched-chain amino acids: physico-chemical properties, industrial synthesis and role in signaling, metabolism and energy production","authors":"Philipp Reifenberg,&nbsp;Aline Zimmer","doi":"10.1007/s00726-024-03417-2","DOIUrl":"10.1007/s00726-024-03417-2","url":null,"abstract":"<div><p>Branched-chain amino acids (BCAAs)—leucine (Leu), isoleucine (Ile), and valine (Val)—are essential nutrients with significant roles in protein synthesis, metabolic regulation, and energy production. This review paper offers a detailed examination of the physico-chemical properties of BCAAs, their industrial synthesis, and their critical functions in various biological processes. The unique isomerism of BCAAs is presented, focusing on analytical challenges in their separation and quantification as well as their solubility characteristics, which are crucial for formulation and purification applications. The industrial synthesis of BCAAs, particularly using bacterial strains like <i>Corynebacterium glutamicum</i>, is explored, alongside methods such as genetic engineering aimed at enhancing production, detailing the enzymatic processes and specific precursors. The dietary uptake, distribution, and catabolism of BCAAs are reviewed as fundamental components of their physiological functions. Ultimately, their multifaceted impact on signaling pathways, immune function, and disease progression is discussed, providing insights into their profound influence on muscle protein synthesis and metabolic health. This comprehensive analysis serves as a resource for understanding both the basic and complex roles of BCAAs in biological systems and their industrial application.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142091425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proline, a unique amino acid whose polymer, polyproline II helix, and its analogues are involved in many biological processes: a review","authors":"Théoneste Umumararungu,&nbsp;Noël Gahamanyi,&nbsp;Janvier Mukiza,&nbsp;Gratien Habarurema,&nbsp;Jonathan Katandula,&nbsp;Alexis Rugamba,&nbsp;Vedaste Kagisha","doi":"10.1007/s00726-024-03410-9","DOIUrl":"10.1007/s00726-024-03410-9","url":null,"abstract":"<div><p>Proline is a unique amino acid in that its side-chain is cyclised to the backbone, thus giving proline an exceptional rigidity and a considerably restricted conformational space. Polyproline forms two well-characterized helical structures: a left-handed polyproline helix (PPII) and a right-handed polyproline helix (PPI). Usually, sequences made only of prolyl residues are in PPII conformation, but even sequences not rich in proline but which are rich in glycine, lysine, glutamate, or aspartate have also a tendency to form PPII helices. Currently, the only way to study unambiguously PPII structure in solution is to use spectroscopies based on optical activity such as circular dichroism, vibrational circular dichroism and Raman optical activity. The importance of the PPII structure is emphasized by its ubiquitous presence in different organisms from yeast to human beings where proline-rich motifs and their binding domains are believed to be involved in vital biological processes. Some of the domains that are bound by proline-rich motifs include SH3 domains, WW domains, GYF domains and UEV domains, etc. The PPII structure has been demonstrated to be essential to biological activities such as signal transduction, transcription, cell motility, and immune response.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11345334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptidomimetic inhibitors of the VEGF-A165/NRP-1 complex obtained by modification of the C-terminal arginine","authors":"Dagmara Tymecka,&nbsp;Patrycja Redkiewicz,&nbsp;Piotr F. J. Lipiński,&nbsp;Aleksandra Misicka","doi":"10.1007/s00726-024-03411-8","DOIUrl":"10.1007/s00726-024-03411-8","url":null,"abstract":"<div><p>Inhibitors of the interaction between Neuropilin-1 (NRP-1) and Vascular Endothelial Growth Factor-A₁₆₅ (VEGF-A₁₆₅) hold significant promise as therapeutic and diagnostic agents directed against cancers overexpressing NRP-1. In our efforts in this field, a few series of strong and fairly stable peptide-like inhibitors of the general formula Lys(Har)¹-Xaa²-Xaa³-Arg⁴ have been previously discovered. In the current work, we focused on Lys(Har)-Dap/Dab-Pro-Arg sequence. The aim was to examine whether replacing C-terminal Arg with its homologs and mimetics would yield more stable yet still potent inhibitors. Upon considering the results of modelling and other factors, ten novel analogues with Xaa⁴ = homoarginine (Har), 2-amino-4-guanidino-butyric acid (Agb), 2-amino-3-guanidino-propionic acid (Agp), citrulline (Cit), 4-aminomethyl-phenylalanine [Phe(4-CH₂-NH₂)] were designed, synthesized and evaluated. Two of the proposed modifications resulted in inhibitors with activity slightly lower [e.g. IC₅₀ = 14.3 μM for Lys(Har)-Dab-Pro-Har and IC₅₀ = 19.8 μM for Lys(Har)-Dab-Pro-Phe(4-CH₂-NH₂)] than the parent compounds [e.g. IC₅₀ = 4.7 μM for Lys(Har)-Dab-Pro-Arg]. What was a surprise to us, the proteolytic stability depended more on position two of the sequence than on position four. The Dab²-analogues exhibited half-life times beyond 60 h. Our results build up the knowledge on the structural requirements that effective VEGF-A₁₆₅/NRP-1 inhibitors should fulfil.</p></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"56 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}