To assess the applicability of serum concentrations of markers of synovial inflammation, cartilage, and bone metabolism in relation to conventional markers of disease activity, bone mineral density ...(BMD) of the hand, and radiographic outcome.
Biochemical markers of collagen tissue metabolism were measured in 72 patients with symmetrically swollen and tender second and third metacarpophalangeal or proximal interphalangeal joints for at least 4 weeks and less than 2 years. At 2 years, 51 patients fulfilled the American College Rheumatology criteria for rheumatoid arthritis (RA) and 21 patients had unclassified polyarthritis. Patients with RA were divided into groups according to the mean disease activity and to magnetic resonance imaging and radiographically detected bone erosions in the hands.
Patients with RA had significantly higher serum concentrations of matrix metalloproteinase-3 (MMP-3) at baseline and higher mean concentrations of serum MMP-3 and pyridinoline (Pyd) during the first 6 and 12 months than patients with unclassified polyarthritis. RA patients with persistent disease activity and erosive disease had significantly higher concentrations of serum MMP-3 and Pyd than patients with no disease activity or nonerosive disease. Significant mutual correlations between serum MMP-3 and Pyd and C-reactive protein and erythrocyte sedimentation rate were observed. The mean values of MMP-3 and Pyd correlated significantly to the alpha coefficient of the digital x-ray radiogrammetry (DXR-BMD).
Serum MMP-3 and Pyd varied according to disease activity, periarticular osteoporosis measured by DXR, and radiographic outcome, and thus appear to supplement the conventional markers of disease activity for monitoring patients with RA.
We used phage display to generate surrogate peptides that define the hotspots involved in protein-protein interaction between insulin and the insulin receptor. All of the peptides competed for ...insulin binding and had affinity constants in the high nanomolar to low micromolar range. Based on competition studies, peptides were grouped into non-overlapping Sites 1, 2, or 3. Some Site 1 peptides were able to activate the tyrosine kinase activity of the insulin receptor and act as agonists in the insulin-dependent fat cell assay, suggesting that Site 1 marks the hotspot involved in insulin-induced activation of the insulin receptor. On the other hand, Site 2 and 3 peptides were found to act as antagonists in the phosphorylation and fat cell assays. These data show that a peptide display can be used to define the molecular architecture of a receptor and to identify the critical regions required for biological activity in a site-directed manner.
Doppelt eingeschränkt: Eine neue, konformativ stark eingeschränkte α‐L‐LNA‐Modifikation (α‐L‐LNA=α‐L‐locked nucleic acid) wurde synthetisiert, in welcher der Zucker‐Furanosering in einer ...N‐Typ‐Konfiguration fixiert und die Rotation um den Torsionswinkel γ eingeschränkt ist (siehe Schema). Diese neue Modifikation erhöht die Thermostabilität eines Oligonucleotidduplex gegenüber dem Einsatz nur einer Einschränkung.
A Catalyst pharmacophore model has been developed for the benzodiazepine site within the GABA
A receptor complex. The model is based on a pharmacophore model originally proposed by Cook and ...co-workers (Drug Des. Discovery 1995, 12, 193–248) and further developed by Kahnberg et al. (J. Med. Chem. 2002, 45, 4188–4201). The Catalyst pharmacophore model has been validated by using a series of flavonoids with varying affinities for the benzodiazepine receptor and has then been used as a search query in database searching with the aim of finding novel structures which have the possibility to be modified into novel lead compounds. Five of the hits from the database searching were purchased and their affinities for the benzodiazepine site of the GABA
A receptor were determined. Two of the compounds displayed
K
i
values below 10
μM. The substance showing highest potency in-vitro displayed an affinity of 121
nM making it an interesting compound for optimization. The false positive compounds (
K
i
values >10
μM affinities) have been analysed in terms of conformational energy penalties and possibilities for hydrogen bond interactions. The analysis clearly demonstrates the need for post processing of Catalyst hits.
A 5'-C-allylthymidine derivative was prepared from thymidine by the application of a stereoselective allylation procedure and its 5'(S)-configuration was confirmed. From this nucleoside derivative, ...appropriately protected building blocks were prepared and coupled using standard phosphoramidite chemistry to afford a dinucleotide with two 5'-C-allylgroups. This molecule was used as a substrate for a ring-closing metathesis (RCM) reaction and after deprotection, a 1 : 1 mixture of E- and Z-isomers of a cyclic dinucleotide with an unsaturated 5'-C-to-5'-C connection was obtained. Alternatively, a hydrogenation of the double bond and deprotection afforded a saturated cyclic dinucleotide. An advanced NMR-examination confirmed the constitution of this molecule and indicated a restriction in its overall conformational freedom. After variation of the protecting group strategy, a phosphoramidite building block of the saturated cyclic dinucleotide with the 5'-O-position protected as a pixyl ether and the phosphate protected as a methyl phosphotriester was obtained. This building block was used in the preparation of two 14-mer oligonucleotides with a central artificial bend due to the cyclic dinucleotide moiety. These were found to destabilise duplexes, slightly destabilise bulged duplexes but, to some extent, stabilise a three-way junction in high Mg(2+)-concentrations.
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