Chronic pain is an undertreated epidemic affecting quality of life in at least 20% of the global population, and CNS-related side effects, tolerance, and addiction are common features of current ...medications. α-Conotoxin Vc1.1 potently elicits prolonged analgesia in preclinical chronic constriction injury and chronic visceral hypersensitivity models of neuropathic pain. A backbone-cyclized variant, cVc1.1, exhibits superior in vitro stability and is orally active, but its in vivo half-life and disposition, both critical in informing drug candidate progression, remain unexplored. Here, we investigate the pharmacological influence of the peptidic bridge differentiating linear and cyclic Vc1.1 in various preclinical PK/PD rodent models. While previous in vitro studies had indicated cyclization conferred increased stability for cVc1.1, in vivo the peptides exhibited similar half-lives and oral bioavailabilities. The ratios of free drug exposure metrics (Cmax × fu,p and AUC0-inf × fu,p) following oral dosing vs. their respective in vitro IC50s at the GABAB receptor were comparable for Vc1.1 and cVc1.1, indicating similar drug efficiency indexes. MALDI imaging, radiolabel, and LC-MS biodistribution studies of cVc1.1 in rodents demonstrated that the intact cyclopeptide and several metabolites persist in the GI tract for at least 4 h, long after the plasma levels of the intact peptide had fallen below the target IC50. Biodistribution analyses of IV administered 125I-labelled cVc1.1 revealed accumulation primarily in the kidneys consistent with renal elimination, and combined with insignificant uptake in brain, suggested a low likelihood of CNS-related side effects.
•cVc1.1 and Vc1.1 exhibit low oral bioavailability and similar half-lives in rat PK.•MALDI imaging demonstrates cVc1.1 in the GI tract for >4 h post oral dosing.•cVc1.1 exhibits negligible penetration into the brain.•Drug efficiency indices of cVc1.1 and Vc1.1 are similar to marketed peptide drugs.•Conotoxins are potent neuroactive peptides with potential for the treatment of pain.
Many analogues of the glycolipid alpha-galactosylceramide (α-GalCer) are known to activate iNKT cells through their interaction with CD1d-expressing antigen-presenting cells, inducing the release of ...Th1 and Th2 cytokines. Because of iNKT cell involvement and associated Th1/Th2 cytokine changes in a broad spectrum of human diseases, the design of iNKT cell ligands with selective Th1 and Th2 properties has been the subject of extensive research. This search for novel iNKT cell ligands requires refined structural insights. Here we will visualize the chemical space of 333 currently known iNKT cell activators, including several newly tested analogues, by more than 3000 chemical descriptors which were calculated for each individual analogue. To evaluate the immunological responses we analyzed five different cytokines in five different test-systems. We linked the chemical space to the immunological space using a system biology computational approach resulting in highly sensitive and specific predictive models. Moreover, these models correspond with the current insights of iNKT cell activation by α-GalCer analogues, explaining the Th1 and Th2 biased responses, downstream of iNKT cell activation. We anticipate that such models will be of great value for the future design of iNKT cell agonists.
Exploration of the Medicinal Peptide Space Gevaert, Bert; Stalmans, Sofie; Wynendaele, Evelien ...
Protein and peptide letters,
01/2016, Letnik:
23, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The chemical properties of peptide medicines, known as the 'medicinal peptide space' is considered a multi-dimensional subset of the global peptide space, where each dimension represents a chemical ...descriptor. These descriptors can be linked to biofunctional, medicinal properties to varying degrees. Knowledge of this space can increase the efficiency of the peptide-drug discovery and development process, as well as advance our understanding and classification of peptide medicines. For 245 peptide drugs, already available on the market or in clinical development, multivariate dataexploration was performed using peptide relevant physicochemical descriptors, their specific peptidedrug target and their clinical use. Our retrospective analysis indicates that clusters in the medicinal peptide space are located in a relatively narrow range of the physicochemical space: dense and empty regions were found, which can be explored for the discovery of novel peptide drugs.
Lipopeptides are currently re-emerging as an interesting subgroup in the peptide research field, having historical applications as antibacterial and antifungal agents and new potential applications ...as antiviral, antitumor, immune-modulating and cell-penetrating compounds. However, due to their specific structure, chromatographic analysis often requires special buffer systems or the use of trifluoroacetic acid, limiting mass spectrometry detection. Therefore, we used a traditional aqueous/acetonitrile based gradient system, containing 0.1% （m/v） formic acid, to separate four pharmaceutically relevant lipopeptides （polymyxin B1, caspofungin, daptomycin and gramicidin A1）, which were selected based upon hierarchical cluster analysis （HCA） and principal component analysis （PCA）.
In total, the performance of four different C18 columns, including one UPLC column, were evaluated using two parallel approaches. First, a Derringer desirability function was used, whereby six single and multiple chromatographic response values were rescaled into one overall D-value per column. Using this approach, the YMC Pack Pro C18 column was ranked as the best column for general MS-compatible lipopeptide separation. Secondly, the kinetic plot approach was used to compare the different columns at different flow rate ranges. As the optimal kinetic column performance is obtained at its maximal pressure, the length elongation factor λ（Pmax/Pexp） was used to transform the obtained experimental data （retention times and peak capacities） and construct kinetic performance limit （KPL） curves, allowing a direct visual and unbiased comparison of the selected columns, whereby the YMC Triart C18 UPLC and ACE C18 columns performed as best. Finally, differences in column performance and the （dis）advantages of both approaches are discussed.
Blood-brain barrier peptides (BBPs) have a large range of biomedical applications since they can cross the blood-brain barrier based on different mechanisms. As experimental methods for the ...identification of BBPs are laborious and expensive, computational approaches are necessary to be developed for predicting BBPs. In this work, we describe a computational method, BBPpred (blood-brain barrier peptides prediction), that can efficiently identify BBPs using logistic regression. We investigate a wide variety of features from amino acid sequence information, and then a feature learning method is adopted to represent the informative features. To improve the prediction performance, seven informative features are selected for classification by eliminating redundant and irrelevant features. In addition, we specifically create two benchmark data sets (training and independent test), which contain a total of 119 BBPs from public databases and the literature. On the training data set, BBPpred shows promising performances with an AUC score of 0.8764 and an AUPR score of 0.8757 using the 10-fold cross-validation. We also test our new method on the independent test data set and obtain a favorable performance. We envision that BBPpred will be a useful tool for identifying, annotating, and characterizing BBPs. BBPpred is freely available at http://BBPpred.xialab.info.
This study performs an environmental risk assessment (ERA) of the anthelmintic medicine albendazole (ABZ) in the eastern African region. A systematic literature search strategy was applied to obtain ...quantitative information on the physicochemical characteristics, the metabolization-fate, the ecotoxicity and the environmental occurrence in different countries worldwide serving as model regions. In addition, insilico tools were employed to obtain data on physicochemical characteristics and toxic hazards of ABZ and its metabolites. Moreover, ERA models were used to predict environmental concentrations in different compartments and compare them with the measured environmental concentrations. Finally, the environmental risk of ABZ in the eastern Africa was estimated by calculating the risk quotient (RQ), and its uncertainty estimated by Monte Carlo simulation. The predicted environmental concentrations of ABZ in surface water in the model region based on consumption (1.6–267 ng/L) were within the range of values obtained from the measured environmental concentrations of the same region (0.05–101,000 ng/L). Using these models with adapted input variables for eastern Africa, the predicted surface water concentration in that region was 19,600 ± 150 ng/L (95% CI). The calculated soil concentrations of ABZ in the model regions and the eastern Africa were found to be 0.057 ± 0.0 μg/kg and 0.022 ± 0.0 μg/kg, respectively. The environmental risk expressed as risk quotient of ABZ in eastern Africa estimated for the aquatic compartment (146 ± 1) indicated a significant environmental risk calling on appropriate actions from the competent authorities to reduce this risk in this region.
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•Anthelminthics present an environmental risk in low-income countries.•Physico-chemical characteristics and metabolites of albendazole were summarized.•Approaches applied to estimate PECs of albendazole yield consistent results.•Relatively low dose albendazole causes toxicity on aquatic and soil organisms.•Albendazole poses a significant environmental risk in eastern Africa.
Different fused-core stationary phase chemistries（C18,Amide,Phenyl-hexyl and Peptide ES-C18） were used for the analysis of 21 structurally representative model peptides.In addition,the effects of the ...mobile phase composition（ACN or MeOH as organic modifier;formic acid or acetic acid,as acidifying component） on the column selectivity,peak shape and overall chromatographic performance were evaluated.The RP-amide column,combined with a formic acid-acetonitrile based gradient system,performed as best.A peptide reversed-phase retention model is proposed,consisting of 5 variables：log SumAA,log Sv,clog P,log nHDon and log nHAcc.Quantitative structure-retention relationship（QSRR） models were constructed for 16 different chromatographic systems.The accuracy of this peptide retention model was demonstrated by the comparison between predicted and experimentally obtained retention times,explaining on average 86% of the variability.Moreover,using an external set of 5 validation peptides,the predictive power of the model was also demonstrated.This peptide retention model includes the novel in-silico calculated amino acid descriptor,AA,which was calculated from log P,3D-MoRSE,RDF and WHIM descriptors.
Peptides are becoming an important class of molecules in the pharmaceutical field. Closely related peptide-impurities in peptides are inherent to the synthesis approach and have demonstrated to ...potentially mask biomedical experimental results. Quorum sensing peptides are attracting high interest in R＆D and therefore a representative set of quorum sensing peptides, with a requested purity of at least 95.0%, was evaluated for their purity and nature of related impurities. In-house quality control （QC） revealed a large discrepancy between the purity levels as stated on the supplier＇s certificate of analysis and our QC results. By using our QC analysis flowchart, we demonstrated that only 44.0% of the peptides met the required purity. The main compound of one sample was even found to have a different structure compared to the desired peptide. We also found that the majority of the related impurities were lacking amino acid（s） in the desired peptide sequence. Relying on the certificates of analysis as provided by the supplier might have serious consequences for peptide research, and peptide-researchers should implement and maintain a thorough in-house QC.
The expression of certain bacterial genes is regulated in a cell-density dependent way, a phenomenon called quorum sensing. Both Gram-negative and Gram-positive bacteria use this type of ...communication, though the signal molecules (auto-inducers) used by them differ between both groups: Gram-negative bacteria use predominantly
-acyl homoserine lacton (AHL) molecules (autoinducer-1, AI-1) while Gram-positive bacteria use mainly peptides (autoinducer peptides, AIP or quorum sensing peptides). These quorum sensing molecules are not only involved in the inter-microbial communication, but can also possibly cross-talk directly or indirectly with their host. This review summarizes the currently applied analytical approaches for quorum sensing identification and quantification with additionally summarizing the experimentally found
concentrations of these molecules in humans.
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