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- Becker, K., et al.
(författare)
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Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
- 2021
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Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
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Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. © 2021 The Author(s)
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- Grigorjeva, Liene, et al.
(författare)
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Semisynthesis of Libiguin A and Its Analogues by Trans-Lactonization of Phragmalin
- 2014
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 79:9, s. 4148-4153
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Tidskriftsartikel (refereegranskat)abstract
- Libiguins are limonoids with highly potent sexual activity enhancing effects, originally isolated from the Madagascarian Meliaceae species Neobeguea mahafalensis, where they exist in only minute quantities. Their low natural abundance has hampered mapping of their biological effects. Here we describe an approach to the semisynthesis of libiguin A and its close analogues 1-3 starting from phragmalin, which is a limonoid present in high amounts in a commercially cultivated Meliaceae species, Chukrasia tabularis, allowing the preparation of libiguins in appreciable quantities.
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- Hosia, W., et al.
(författare)
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Folding into a ß-Hairpin Can Prevent Amyloid Fibril-Formation
- 2004
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 43:16, s. 4655-4661
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Tidskriftsartikel (refereegranskat)abstract
- The tetrapeptide KFFE is one of the shortest amyloid fibril-forming peptides described. Herein, we have investigated how the structural environment of this motif affects polymerization. Using a turn motif (YNGK) or a less rigid sequence (AAAK) to fuse two KFFE tetrapeptides, we show by several biophysical methods that the amyloidogenic properties are strongly dependent on the structural environment. The dodecapeptide KFFEAAAKKFFE forms abundant thick fibril bundles. Freshly dissolved KFFEAAAKKFFE is monomeric and shows mainly disordered secondary structure, as evidenced by circular dichroism, NMR spectroscopy, hydrogen/deuterium exchange measurements, and molecular modeling studies. In sharp contrast, the dodecapeptide KFFEYNGKKFFE does not form fibrils but folds into a stable ß-hairpin. This structure can oligomerize into a stable 12-mer and multiples thereof, as shown by size exclusion chromatography, sedimentation analysis, and electrospray mass spectrometry. These data indicate that the structural context in which a potential fibril forming sequence is present can prevent fibril formation by favoring self-limiting oligomerization over polymerization.
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- Liepinsh, E, et al.
(författare)
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NMR structure of human coactosin-like protein
- 2004
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Ingår i: Journal of biomolecular NMR. - : Springer Science and Business Media LLC. - 0925-2738 .- 1573-5001. ; 30:3, s. 353-356
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Modig, Kristofer, et al.
(författare)
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Dynamics of protein and peptide hydration
- 2004
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 126:1, s. 102-114
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Tidskriftsartikel (refereegranskat)abstract
- Biological processes often involve the surfaces of proteins, where the structural and dynamic properties of the aqueous solvent are modified. Information about the dynamics of protein hydration can be obtained by measuring the magnetic relaxation dispersion (MRD) of the water 2 H and 17 0 nuclei or by recording the nuclear Overhauser effect (NOE) between water and protein protons. Here, we use the MRD method to study the hydration of the cyclic peptide oxytocin and the globular protein BPTI in deeply supercooled solutions. The results provide a detailed characterization of water dynamics in the hydration layer at the surface of these biomolecules. More than 95% of the water molecules in contact with the biomolecular surface are found to be no more than two-fold motionally retarded as compared to bulk water. In contrast to small nonpolar molecules, the retardation factor for BPTI showed little or no temperature dependence, suggesting that the exposed nonpolar residues do not induce clathrate-like hydrophobic hydration structures. New NOE data for oxytocin and published NOE data for BPTI were analyzed, and a mutually consistent interpretation of MRD and NOE results was achieved with the aid of a new theory of intermolecular dipolar relaxation that accounts explicitly for the dynamic perturbation at the biomolecular surface. The analysis indicates that water-protein NOES are dominated by long-range dipolar couplings to bulk water, unless the monitored protein proton is near a partly or fully buried hydration site where the water molecule has a long residence time.
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- Muceniece, Ruta, et al.
(författare)
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Beta-MSH inhibits brain inflammation via MC(3)/(4) receptors and impaired NF-kappaB signaling
- 2005
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 169:1-2, s. 13-19
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Tidskriftsartikel (refereegranskat)abstract
- The anti-inflammatory effects of melanocortin peptides have been demonstrated in different inflammation models. This is the first report describing the molecular mechanisms for the beta-MSH-induced suppression of bacterial lipopolisaccharide (LPS)-caused brain inflammation. We found that beta-MSH suppresses LPS-induced nuclear translocation of the transcription factor NF-kappaB, and inhibits the expression of inducible nitric oxide synthase, and the following nitric oxide overproduction in the brain, in vivo. Moreover, administering the preferentially MC(4) receptor selective antagonist HS014 blocked completely these effects, suggesting a tentative MC(4) receptor mediated mechanism of action for the beta-MSH. However, as HS014 shows quite low selectivity vis-à-vis the MC(3) receptor, a role for the MC(3) receptor cannot be excluded. In conclusion, our results show that beta-MSH is capable of inhibiting brain inflammation via activation of melanocortin receptors, of the subtypes 4 and/or 3.
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| 40. |
- Muceniece, Ruta, et al.
(författare)
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Functional evaluation of THIQ, a melanocortin 4 receptor agonist, in models of food intake and inflammation
- 2007
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 101:6, s. 416-420
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Tidskriftsartikel (refereegranskat)abstract
- The central melanocortinergic system plays an important role in regulating different aspects of energy homeostasis and the immunomodulatory response. In the present study, we evaluated the in vivo activities of food intake suppression and anti-inflammatory activity of THIQ, which has been proposed to possess high and selective melanocortin-4 receptor agonistic activity in vitro. The results showed that THIQ (0.1, 0.3 and 1 nmol/rat, intracerebroventricularly) is less effective in reducing food intake and body weights of rats than the non-selective melanocortin receptor agonist melanotan II. Electron paramagnetic resonance measurements in mice brain tissue showed that THIQ at doses of 0.001 and 0.01 nmol/mouse (intracisternally) increased the concentration of nitric oxide, which is not typical for melanocortin receptor agonists. In an experimental brain inflammation model, THIQ only weakly antagonized lipopolysaccharide-induced nitric oxide overproduction in brain tissue at a dose of 0.01 nmol/mouse. Our findings provide new insight into the in vivo pharmacological profile of the in vitro selective melanocortin-4 receptor agonist THIQ and give grounds for caution when interpreting and predicting melanocortin receptor selective agonist activity in vivo.
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| 41. |
- Muceniece, Ruta, et al.
(författare)
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The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model
- 2006
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 27:6, s. 1443-1450
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Tidskriftsartikel (refereegranskat)abstract
- Melanocortins possess strong anti-inflammatory effects acting in the central nervous system via inhibition of the production of nitric oxide (NO) during brain inflammation. To shed more light into the role of melanocortin (MC) receptor subtypes involved we synthesized and evaluated some novel peptides, modified in the melanocyte-stimulating hormone (MSH) core structure, natural MCs and known MC receptor selective peptides - MS05, MS06. Since the study included both selective, high affinity binders and the novel peptides, it was possible to do the correlation analysis of binding activities and the NO induction-related anti-inflammatory effect of the peptides. beta-MSH, gamma1-MSH, gamma2-MSH, alpha-MSH, MS05, Ac-MS06 and Ac-[Ser12]MS06 caused dose dependent inhibition of the lipopolysaccharide (LPS)-induced increase of NO overproduction in the mice forebrain whereas MSH core modified peptides Ac-[Asp9,Ser12]MS06, [Asp9]alpha-MSH and [Asp16]beta-MSH were devoid of this effect in doses up to 10 nmol per mouse. When the minimal effective dose required for inhibition of NO production was correlated with the in vitro binding activity to MC receptor subtypes a strong and significant correlation was found for the MC3 receptor (r = 0.90; p = 0.0008), whereas weak correlation was present for the other receptors. Our results suggest that the MC3 receptor is the major player in mediating the anti-inflammatory activity of MCs in the central nervous system.
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| 42. |
- Mutulis, Felikss, et al.
(författare)
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N-alkylated dipeptide amides and related structures as imitations of the melanocortins' active core
- 2005
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 26:10, s. 1997-2016
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Tidskriftsartikel (refereegranskat)abstract
- Thirty-three low molecular mass structures combining both peptide and peptoid features were prepared and tested on human melanocortin receptors MC1,3-5R. Most of them displayed low micromolar activity with preference for diamines, guanidino and 2-naphthyl derivatives compared to monoacetylated, amino and 3-indolyl counterparts. Some contained L- or D-histidine residues, but the change did not influence affinity. QSAR modelling yielded excellent models for the MC3-5 receptors explaining R2Y=0.89-0.91 and predicting Q2=0.77-0.80 of the affinity variations. One compound displayed MC1R selectivity (13-fold and more). An NMR study of showed that it exists as a mixture of four rotamers at its tertiary amide bonds. Comparisons with earlier data for melanocortin core tetrapeptide analogues indicate that the novel peptide-peptoids interact with the melanocortin receptors in a different way.
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| 44. |
- Mutulis, Felikss, et al.
(författare)
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Oligomerization of indole derivatives with incorporation of thiols
- 2008
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 13:8, s. 1846-63
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Tidskriftsartikel (refereegranskat)abstract
- Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.g. 1,2-ethanedithiol, in the presence of trifluoroacetic acid to yield adducts such as 3-[2-(2-amino-5-carboxyphenyl)-1-(2-mercaptoethylthio)ethyl]-1Hindole-5-carboxylic acid. Parallel formation of dimers, such as 2,3-dihydro-1H,1'H-2,3'-biindole-5,5'-dicarboxylic acid and trimers, such as 3,3'-[2-(2-amino-5-carboxyphenyl) ethane-1,1-diyl]bis(1H-indole-5-carboxylic acid) of the indole derivatives was also observed. Reaction of a mixture of indole and indole-5-carboxylic acid with 2-phenylethanethiol proceeded in a regioselective way, affording 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H-indole-5-carboxylic acid. An additional product of this reaction was 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-2,3-dihydro-1H,1'H-2,3'-biindole-5'-carboxylic acid, which upon standing in DMSO-d6 solution gave 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H,1'H-2,3'-biindole-5'-carboxylic acid. Structures of all compounds were elucidated by NMR, and a mechanism for their formation was suggested.
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