Glikoznanost - nova smjernica u suvremenom dizajniranju lijekova

Glycans are the most abundant and most diverse biopolymers in nature. Because of their highly specific interactions with physiological receptors, they participate in many crucial biological processes. All these processes are potential targets for therapeutic intervention, and carbohydrate-based drugs are rapidly being taken up by the modern biotechnology and pharmaceutical industry. Recent developments in the field of glycobiology have overcome the problem of glycan analysis and synthesis; and many compounds based on carbohydrates are now in various stages of clinical trials. This article presents glycoproteins in a new light, as an important biopharmaceutical target, giving an overview of their potential use as therapeutic glycoproteins and proteoglycans, inflammation blockers, cancer therapeutics and vaccines, inhibitors of pathogenic microbes, viral inhibitors and potential aids in the treatment of lysosomal diseases, neurological diseases and transplantation rejection.Glikani su najrasprostranjeniji i najraznolikiji biopolimeri prisutni u prirodi. Zbog svojih interakcija s fiziološkim receptorima sudjeluju u mnogim ključnim biološkim procesima. Svi ti procesi potencijalna su meta terapeutskih intervencija pa lijekovi bazirani na ugljikohidratima nalaze svoje mjesto u suvremenoj biotehnologiji i farmaceutskoj industriji. Razvojem glikobiologije prevladan je problem sinteze i analize glikana pa su mnogi spojevi bazirani na ugljikohidratnim strukturama trenutno u različitim fazama kliničkih ispitivanja. Ovaj članak predstavlja glikoproteine u novom svjetlu, kao važne biofarmaceutske ciljeve, dajući pregled njihove potencijalne primjene kao terapijskih glikoproteina i proteoglikana, inhibitora upale, lijekova i vakcina u liječenju tumora, inhibitora patogenih mikroorganizama i virusa, te potencijalnih sredstava u liječenju lizosomskih i neuroloških bolesti te transplantacijskih reakcija

Glycoconjugates and lectins in development of new medications

Glikani su najzastupljeniji i najraznolikiji biopolimeri u prirodi. Putem specifičnih interakcija sa svojim fiziološkim receptorima oni sudjeluju u brojnim ključnim fiziološkim procesima. Svi ti procesi predstavljaju potencijalne mete za terapeutske intervencije te suvremena biotehnologija i farmaceutska industrija ubrzano razvija lijekove zasnovane na ugljikohidratnim strukturama. Napredak glikobiologije omogućio je analizu i sintezu glikanskih struktura i danas su brojni takvi lijekovi u različitim fazama kliničkih ispitivanja. U ovom su članku glikoproteini prikazani kao važne potencijalne farmaceutske mete, a prikazanje i pregled potencijalne primjene glikoproteina i proteoglikana kao blokatora upale i infekcije, cjepiva, lijekova protiv tumora, te u terapiji lizosomskih bolesti, neuroloških bolesti i odbacivanja transplantata.Glycans are the most abundant and most diverse biopolymers in nature. Because of their highly specific interactions with physiological receptors they participate in many crucial physiological processes. All these processes are potential targets for therapeutic intervention, and carbohydrate-based drugs are rapidly being taken up by the modern biotechnology and pharmaceutical industry. Recent developments in the field of glycobiology have overcome the problem of glycan analysis and synthesis; and now many compounds based on carbohydrates are now in various stages of clinical trials. This article presents glycoproteins in a new light, as an important biopharmaceutical target, giving an overview of their potential use as therapeutic glycoproteins and proteoglycans, inflammation blockers, cancer therapeutics and vaccines, inhibitors of pathogenic microbes, viral inhibitors and potential aids in the treatment of lysosomal diseases, neurological diseases and transplantation rejection

Glycoconjugates and lectins in development of new medications

Glikani su najzastupljeniji i najraznolikiji biopolimeri u prirodi. Putem specifičnih interakcija sa svojim fiziološkim receptorima oni sudjeluju u brojnim ključnim fiziološkim procesima. Svi ti procesi predstavljaju potencijalne mete za terapeutske intervencije te suvremena biotehnologija i farmaceutska industrija ubrzano razvija lijekove zasnovane na ugljikohidratnim strukturama. Napredak glikobiologije omogućio je analizu i sintezu glikanskih struktura i danas su brojni takvi lijekovi u različitim fazama kliničkih ispitivanja. U ovom su članku glikoproteini prikazani kao važne potencijalne farmaceutske mete, a prikazanje i pregled potencijalne primjene glikoproteina i proteoglikana kao blokatora upale i infekcije, cjepiva, lijekova protiv tumora, te u terapiji lizosomskih bolesti, neuroloških bolesti i odbacivanja transplantata.Glycans are the most abundant and most diverse biopolymers in nature. Because of their highly specific interactions with physiological receptors they participate in many crucial physiological processes. All these processes are potential targets for therapeutic intervention, and carbohydrate-based drugs are rapidly being taken up by the modern biotechnology and pharmaceutical industry. Recent developments in the field of glycobiology have overcome the problem of glycan analysis and synthesis; and now many compounds based on carbohydrates are now in various stages of clinical trials. This article presents glycoproteins in a new light, as an important biopharmaceutical target, giving an overview of their potential use as therapeutic glycoproteins and proteoglycans, inflammation blockers, cancer therapeutics and vaccines, inhibitors of pathogenic microbes, viral inhibitors and potential aids in the treatment of lysosomal diseases, neurological diseases and transplantation rejection

Glycosylation Alterations in Multiple Sclerosis Show Increased Proinflammatory Potential

Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the central nervous system (CNS), with unresolved aetiology. Previous studies have implicated N-glycosylation, a highly regulated enzymatic attachment of complex sugars to targeted proteins, in MS pathogenesis. We investigated individual variation in N-glycosylation of the total plasma proteome and of IgG in MS. Both plasma protein and IgG N-glycans were chromatographically profiled and quantified in 83 MS cases and 88 age- and sex-matched controls. Comparing levels of glycosylation features between MS cases and controls revealed that core fucosylation (p = 6.96 × 10−3) and abundance of high-mannose structures (p = 1.48 × 10−2) were the most prominently altered IgG glycosylation traits. Significant changes in plasma protein N-glycome composition were observed for antennary fucosylated, tri- and tetrasialylated, tri- and tetragalactosylated, high-branched N-glycans (p-value range 1.66 × 10−2–4.28 × 10−2). Classification performance of N-glycans was examined by ROC curve analysis, resulting in an AUC of 0.852 for the total plasma N-glycome and 0.798 for IgG N-glycome prediction models. Our results indicate that multiple aspects of protein glycosylation are altered in MS, showing increased proinflammatory potential. N-glycan alterations showed substantial value in classification of the disease status, nonetheless, additional studies are warranted to explore their exact role in MS development and utility as biomarkers

Genome-wide association study identifies _FUT8_ and _ESR2_ as co-regulators of a bi-antennary N-linked glycan A2 (GlcNAc~2~Man~3~GlcNAc~2~) in human plasma proteins

HPLC analysis of N-glycans quantified levels of the biantennary glycan (A2) in plasma proteins of 924 individuals. Subsequent genome-wide association study (GWAS) using 317,503 single nucleotide polymorphysms (SNP) identified two genetic loci influencing variation in A2: FUT 8 and ESR2. We demonstrate that human glycans are amenable to GWAS and their genetic regulation shows sex-specific effects with _FUT 8_ variants explaining 17.3% of the variance in pre-menopausal women, while _ESR2_ variants explained 6.0% of the variance in post-menopausal women

Generation of coherent terahertz pulses in Ruby at room temperature

We have shown that a coherently driven solid state medium can potentially produce strong controllable short pulses of THz radiation. The high efficiency of the technique is based on excitation of maximal THz coherence by applying resonant optical pulses to the medium. The excited coherence in the medium is connected to macroscopic polarization coupled to THz radiation. We have performed detailed simulations by solving the coupled density matrix and Maxwell equations. By using a simple $V$-type energy scheme for ruby, we have demonstrated that the energy of generated THz pulses ranges from hundreds of pico-Joules to nano-Joules at room temperature and micro-Joules at liquid helium temperature, with pulse durations from picoseconds to tens of nanoseconds. We have also suggested a coherent ruby source that lases on two optical wavelengths and simultaneously generates THz radiation. We discussed also possibilities of extension of the technique to different solid-state materials

Fucosylated AGP glycopeptides as biomarkers of HNF1A-Maturity onset diabetes of the young

Aims: We previously demonstrated that antennary fucosylated N-glycans on plasma proteins are regulated by HNF1A and can identify cases of Maturity-Onset Diabetes of the Young caused by HNF1A variants (HNF1A-MODY). Based on literature data, we further postulated that N-glycans with best diagnostic value mostly originate from alpha-1-acid glycoprotein (AGP). In this study we analyzed fucosylation of AGP in subjects with HNF1A-MODY and other types of diabetes aiming to evaluate its diagnostic potential. Methods: A recently developed LC-MS method for AGP N-glycopeptide analysis was utilized in two independent cohorts: a) 466 subjects with different diabetes subtypes to test the fucosylation differences, b) 98 selected individuals to test the discriminative potential for pathogenic HNF1A variants. Results: Our results showed significant reduction in AGP fucosylation associated to HNF1A-MODY when compared to other diabetes subtypes. Additionally, ROC curve analysis confirmed significant discriminatory potential of individual fucosylated AGP glycopeptides, where the best performing glycopeptide had an AUC of 0.94 (95% CI 0.90–0.99). Conclusions: A glycopeptide based diagnostic tool would be beneficial for patient stratification by providing information about the functionality of HNF1A. It could assist the interpretation of DNA sequencing results and be a useful addition to the differential diagnostic process.publishedVersio

Glycomics meets lipidomics - associations of N-glycans with classical lipids, glycerophospholipids, and sphingolipids in three European populations

Recently, high-throughput technologies have been made available which allow the measurement of a broad spectrum of glycomics and lipidomics parameters in many samples. The aim of this study was to apply these methods and investigate associations between 46 glycan and 183 lipid traits measured in blood of 2041 Europeans from three different local populations (Croatia - VIS cohort; Sweden - NSPHS cohort; Great Britain - ORCADES cohort). N-glycans have been analyzed with High Performance Liquid Chromatography (HPLC) and lipids with Electrospray Ionization Tandem Mass Spectrometry (ESI-MS/MS) covering sterol lipids, glycerolipids, glycerophospholipids and sphingolipids in eight subclasses. Overall, 8418 associations were calculated using linear mixed effect models adjusted for pedigree, sex, age and multiple testing. We found 330 significant correlations in VIS. Pearson's correlation coefficient r ranged from −0.27 to 0.34 with corresponding p-values between 1.45 × 10−19 and 4.83 × 10−6, indicating statistical significance. A total of 71 correlations in VIS could be replicated in NSPHS (r = [−0.19; 0.35], p = [4.16 × 10−18; 9.38 × 10−5]) and 31 correlations in VIS were also found in ORCADES (r = [−0.20; 0.24], p = [2.69 × 10−10; 7.55 × 10−5]). However, in total only 10 correlations between a subset of triantennary glycans and unsaturated phosphatidylcholine, saturated ceramide, and sphingomyelin lipids in VIS (r = [0.18; 0.34], p = [2.98 × 10−21; 1.69 × 10−06]) could be replicated in both NSPHS and ORCADES. In summary, the results show strong and consistent associations between certain glycans and lipids in all populations, but also population-specific correlations which may be caused by environmental and genetic differences. These associations point towards potential interactive metabolic pathways

IgG N-glycans are associated with prevalent and incident complications of type 2 diabetes

Aims/Hypothesis:Inflammation is important in the development of type 2 diabetes complications. The N-glycosylation of IgG influences its role in inflammation. To date, the association of plasma IgG N-glycosylation with type 2 diabetes complications has not been extensively investigated. We hypothesised that N-glycosylation of IgG may be related to the development of complications of type 2 diabetes. Methods: In three independent type 2 diabetes cohorts, plasma IgG N-glycosylation was measured using ultra performance liquid chromatography (DiaGene n = 1815, GenodiabMar n = 640) and mass spectrometry (Hoorn Diabetes Care Study n = 1266). We investigated the associations of IgG N-glycosylation (fucosylation, galactosylation, sialylation and bisection) with incident and prevalent nephropathy, retinopathy and macrovascular disease using Cox- and logistic regression, followed by meta-analyses. The models were adjusted for age and sex and additionally for clinical risk factors. Results: IgG galactosylation was negatively associated with prevalent and incident nephropathy and macrovascular disease after adjustment for clinical risk factors. Sialylation was negatively associated with incident diabetic nephropathy after adjustment for clinical risk factors. For incident retinopathy, similar associations were found for galactosylation, adjusted for age and sex. Conclusions: We showed that IgG N-glycosylation, particularly galactosylation and to a lesser extent sialylation, is associated with a higher prevalence and future development of macro- and microvascular complications of diabetes. These findings indicate the predictive potential of IgG N-glycosylation in diabetes complications and should be analysed further in additional large cohorts to obtain the power to solidify these conclusions.</p