16 research outputs found
Oral bioavailability of carbohydrate mimetics : an "in vitro" and "in vivo" evaluation
Carbohydrates play a crucial role in metabolism, cell recognition, cell differentiation, and adhesion processes. Therefore, these molecules represent a potent source for the development of new treatments against many different diseases with an unmet medical need. However, compounds of this class have major inherent drawbacks related to their chemical structure. Carbohydrates are complex and hydrophilic structures with a large polar surface area, which commonly results in poor pharmacokinetic (PK) properties including low oral bioavailability and short plasma half-life due to fast renal clearance. To overcome the poor PK properties of the natural ligands, specific structural modifications have to be implemented in the drug development process from the beginning.
Improvements of newly synthesized compounds have to be constantly monitored with in vitro and in vivo PK measurements, allowing a direct feedback for further structural modifications. To this purpose, a PADMET platform (Physicochemical properties, Absorption, Distribution, Metabolism, Elimination, Toxicity) of in vitro assays, addressing different aspects that influence the PK properties of a molecule was developed and optimized. The intestinal absorption is a major hurdle to achieve sufficient oral bioavailability of carbohydrate mimetics and therefore,the focus of this work is set on the permeability of carbohydrate mimetic by passive permeation or active transport.
In this thesis, three different targets for the development of potent lead structures starting from natural carbohydrates are discussed:
• E-selectin is a lectin expressed on endothelial cells upon an inflammatory stimulus and is crucial for the recruitment of leukocytes to the side of inflammation. Therefore, E- selectin has been recognized as a potent target for the treatment of various diseases with an inflammatory component. The carbohydrate epitope recognized by E-selectin is the tetrasaccharide sialyl Lewisx (sLex). For the treatment of chronic inflammatory diseases, an oral administration is of interest. However, the development of an orally bioavailable E-selectin antagonist from sLex is challenging due to its chemical properties. To overcome the hurdle of insufficient intestinal absorption, an ester prodrug strategy and a bioisosteric replacement were followed and further evaluated by in vivo PK studies in mice. The ester prodrug approach resulted in insufficient oral bioavailability but improvement of the apparent plasma half-life, whereas the bioisosteric approach lead to the first orally bioavailable E-selectin antagonist.
• Uropathogenic Eschericha coli (UPEC) are the main cause of urinary tract infections(UTI). UPEC are expressing the virulence factor FimH on the distal tip of type 1 fimbriae, which binds to mannosides on the luminal surface of the bladder to prevent bacteria from being washed out by urine flow. FimH is therefore a promising target for an antiadhesive treatment of UTIs in order to replace current antibiotic treatment strategies. In this work, known biphenyl-α-D-manno-pyranosides were further developed in terms of affinity and in vitro PK properties.
• Sialic acids bound or in free circulation are regulated by sialyltransferases and neuraminidases (NEU). Selective inhibitors for the human neuraminidase NEU3 is of interest to study the physiological and pathophysiological role of neuraminidases and further evaluate the potential to develop therapeutics. Here, the development of specific NEU3 inhibitors, as well as the attempt to optimize their PK properties is reported
Holocene global mean surface temperature, a multi-method reconstruction approach
An extensive new multi-proxy database of paleo-temperature time series (Temperature 12k) enables a more robust analysis of global mean surface temperature (GMST) and associated uncertainties than was previously available. We applied five different statistical methods to reconstruct the GMST of the past 12,000 years (Holocene). Each method used different approaches to averaging the globally distributed time series and to characterizing various sources of uncertainty, including proxy temperature, chronology and methodological choices. The results were aggregated to generate a multi-method ensemble of plausible GMST and latitudinal-zone temperature reconstructions with a realistic range of uncertainties. The warmest 200-year-long interval took place around 6500 years ago when GMST was 0.7 °C (0.3, 1.8) warmer than the 19 th Century (median, 5 th , 95 th percentiles). Following the Holocene global thermal maximum, GMST cooled at an average rate −0.08 °C per 1000 years (−0.24, −0.05). The multi-method ensembles and the code used to generate them highlight the utility of the Temperature 12k database, and they are now available for future use by studies aimed at understanding Holocene evolution of the Earth system
2 deoxyglycosylation towards more effective and bioavailable neuroprotective molecules inspired by nature
Abstract
The neuroprotective role of natural polyphenols is well established but phenolics poor water solubility affects their bioavailability and bioactivity. Aiming to overcome this issue, we were encouraged to investigate the 2-deoxyglycosylation of natural or nature inspired neuroprotective molecules, using glycals as easily accessed glycosyl donors. This robust methodology allowed the generation of a set of new resveratrol and caffeic acid ester glycosides, envisioning more effective and bioavailable compounds. Resveratrol 2-deoxyglycosides were more effective at protecting the neuronal cells from peroxide-induced cytotoxicity than resveratrol itself, while the caffeic acid ester glycoside also showed extraordinary neuroprotection activity. Coefficient partition measurements demonstrated the moderate lipophilicity of resveratrol glycosides, which Log D values are typical of a central nervous system (CNS) drug and ideal for blood-brain barrier (BBB) penetration. Passive permeation assessed by the parallel artificial membrane permeability assay (PAMPA) revealed that 2,6-dideoxy-l-arabino-hexopyranosides were more effective than 2-deoxy-d-arabino-hexopyranosides. The lack of toxicity of the neuroprotective glycosides and their promising physicochemical properties revealed the usefulness of sugar coupling towards the modulation of natural product properties and bioactivity
A global database of Holocene paleotemperature records
A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format.Fil: Kaufman, Darrell. Northern Arizona University.; Estados UnidosFil: McKay, Nicholas. Northern Arizona University.; Estados UnidosFil: Routson, Cody. Northern Arizona University.; Estados UnidosFil: Erb, Michael. Northern Arizona University.; Estados UnidosFil: Davis, Basil. University Of Lausanne; SuizaFil: Heiri, Oliver. University Of Basel; SuizaFil: Jaccard, Samuel. University Of Bern; SuizaFil: Tierney, Jessica. University of Arizona; Estados UnidosFil: Dätwyler, Christoph. University Of Bern; SuizaFil: Axford, Yarrow. Northwestern University; Estados UnidosFil: Brussel, Thomas. University of Utah; Estados UnidosFil: Cartapanis, Olivier. University Of Bern; SuizaFil: Chase, Brian. Universite de Montpellier; FranciaFil: Dawson, Andria. Mount Royal University; CanadáFil: de Vernal, Anne. Université du Québec a Montreal; CanadáFil: Engels, Stefan. University of London; Reino UnidoFil: Jonkers, Lukas. University Of Bremen; AlemaniaFil: Marsicek, Jeremiah. University of Wisconsin-Madison; Estados UnidosFil: Moffa Sánchez, Paola. University of Durham; Reino UnidoFil: Morrill, Carrie. University of Colorado; Estados UnidosFil: Orsi, Anais. Université Paris-Saclay; FranciaFil: Rehfeld, Kira. Heidelberg University; AlemaniaFil: Saunders, Krystyna. Australian Nuclear Science And Technology Organisation; AustraliaFil: Sommer, Philipp. University Of Lausanne; SuizaFil: Thomas, Elizabeth. University At Buffalo; Estados UnidosFil: Tonello, Marcela Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Tóth, Mónika. Balaton Limnological Institute; HungríaFil: Vachula, Richard. Brown University; Estados UnidosFil: Andreev, Andrei. Alfred Wegener Institut Helmholtz Centre for Polar and Marine Research; AlemaniaFil: Bertrand, Sebastien. Ghent University; BélgicaFil: Massaferro, Julieta. Administración de Parques Nacionales. Parque Nacional "Nahuel Huapi"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin
Prodruggability of Carbohydrates - Oral FimH Antagonists
The bacterial lectin FimH is a promising therapeutic target for the nonantibiotic prevention and treatment of urinary tract infections. In this communication, an ester prodrug approach is described to achieve oral bioavailability for FimH antagonists. By introducing short-chain acyl promoieties at the C-6 position of a biphenyl α- d -mannopyranoside, prodrugs with an excellent absorption potential were obtained. The human carboxylesterase 2 was identified as a main enzyme mediating rapid bioconversion to the active principle. Despite their propensity to hydrolysis within the enterocytes during absorption, these ester prodrugs present a considerable progress in the development of orally available FimH antagonists
Activities of N,N'-Diarylurea MMV665852 analogs against Schistosoma mansoni
There is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852, N,N'-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationships of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adult Schistosoma mansoni worms in vitro. Active compounds were evaluated with a cytotoxicity assay, in silico calculations, metabolic stability studies, and an in vivo assay with mice harboring adult S. mansoni worms. Of the 46 compounds tested at 33.3 μM, 13 and 14 compounds killed NTS and adult worms, respectively, within 72 h. Nine compounds had 90% inhibitory concentrations (IC90s) of ≤10 μM against adult worms, with selectivity indexes of ≥2.8. Their physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption. Their metabolic stabilities ranged from low to high. Despite satisfactory in vitro results and in silico predictions, only one compound resulted in a statistically significant worm burden reduction (66%) after administration of a single oral dose of 400 mg/kg of body weight to S. mansoni-infected mice. Worm burden reductions of 0 to 43% were observed for the remaining eight compounds tested. In conclusion, several analogs of the N,N'-diarylurea MMV665852 had high efficacy against S. mansoni in vitro and favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy observed in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties
Selective Inhibitors of Human Neuraminidase 3
Human neuraminidases (NEU) are associated with human diseases including cancer, atherosclerosis, and diabetes. To obtain small molecule inhibitors as research tools for the study of their biological functions, we designed a library of 2-deoxy-2,3-didehydro- N-acetylneuraminic acid (DANA) analogues with modifications at C4 and C9 positions. This library allowed us to discover selective inhibitors targeting the human NEU3 isoenzyme. Our most selective inhibitor for NEU3 has a K; i; of 320 ± 40 nM and a 15-fold selectivity over other human neuraminidase isoenzymes. This inhibitor blocks glycolipid processing by NEU3 in vitro. To improve their pharmacokinetic properties, various esters of the best inhibitors were synthesized and evaluated. Finally, we confirmed that our best compounds exhibited selective inhibition of NEU orthologues from murine brain
Improvement of Aglycone π-Stacking Yields Nano- to Subnanomolar FimH Antagonists
Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d-mannosides leads to compounds with perfect π-π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to subnanomolar KDs for the low- and the high-affinity state, respectively. The face-to-face alignment of the perfluorinated biphenyl of FimH ligands and Tyr48 was confirmed by crystal structures as well as 1H,15N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability