540 Chemie und zugeordnete Wissenschaften
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While many proteins are known clients of heat shock protein 90 (Hsp90), it is unclear whether the transcription factor, thyroid hormone receptor beta (TRb), interacts with Hsp90 to control hormonal perception and signaling. Higher Hsp90 expression in mouse fibroblasts was elicited by the addition of triiodothyronine (T3). T3 bound to Hsp90 and enhanced adenosine triphosphate (ATP) binding of Hsp90 due to a specific binding site for T3, as identified by molecular docking experiments. The binding of TRb to Hsp90 was prevented by T3 or by the thyroid mimetic sobetirome. Purified recombinant TRb trapped Hsp90 from cell lysate or purified Hsp90 in pull-down experiments. The affinity of Hsp90 for TRb was 124 nM. Furthermore, T3 induced the release of bound TRb from Hsp90, which was shown by streptavidin-conjugated quantum dot (SAv-QD) masking assay. The data indicate that the T3 interaction with TRb and Hsp90 may be an amplifier of the cellular stress response by blocking Hsp90 activity.
Nanomedicine strategies were first adapted and successfully translated to clinical application for diseases, such as cancer and diabetes. These strategies would no doubt benefit unmet diseases needs as in the case of leishmaniasis. The latter causes skin sores in the cutaneous form and affects internal organs in the visceral form. Treatment of cutaneous leishmaniasis (CL) aims at accelerating wound healing, reducing scarring and cosmetic morbidity, preventing parasite transmission and relapse. Unfortunately, available treatments show only suboptimal effectiveness and none of them were designed specifically for this disease condition. Tissue regeneration using nano-based devices coupled with drug delivery are currently being used in clinic to address diabetic wounds. Thus, in this review, we analyse the current treatment options and attempt to critically analyse the use of nanomedicine-based strategies to address CL wounds in view of achieving scarless wound healing, targeting secondary bacterial infection and lowering drug toxicity.
Process-induced changes in the morphology of biodegradable polybutylene adipate terephthalate (PBAT) and polylactic acid (PLA) blends modified with various multifunctional chainextending cross-linkers (CECLs) are presented. The morphology of unmodified and modified films produced with blown film extrusion is examined in an extrusion direction (ED) and a transverse direction (TD). While FTIR analysis showed only small peak shifts indicating that the CECLs modify the molecular weight of the PBAT/PLA blend, SEM investigations of the fracture surfaces of blown extrusion films revealed their significant effect on the morphology formed during the processing. Due to the combined shear and elongation deformation during blown film extrusion, rather spherical PLA islands were partly transformed into long fibrils, which tended to decay to chains of elliptical islands if cooled slowly. The CECL introduction into the blend changed the thickness of the PLA fibrils, modified the interface adhesion, and altered the deformation behavior of the PBAT matrix from brittle to ductile. The results proved that CECLs react selectively with PBAT, PLA, and their interface. Furthermore, the reactions of CECLs with PBAT/PLA induced by the processing depended on the deformation directions (ED and TD), thus resulting in further non-uniformities of blown extrusion films.
Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.
Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.
The white ground crater by the Phiale Painter (450–440 BC) exhibited in the “Pietro Griffo” Archaeological Museum in Agrigento (Italy) depicts two scenes from Perseus myth. The vase is of utmost importance to archaeologists because the figures are drawn on a white background with remarkable daintiness and attention to detail. Notwithstanding the white ground ceramics being well documented from an archaeological and historical point of view, doubts concerning the compositions of pigments and binders and the production technique are still unsolved. This kind of vase is a valuable rarity, the use of which is documented in elitist funeral rituals. The study aims to investigate the constituent materials and the execution technique of this magnificent crater. The investigation was carried out using non-destructive and non-invasive techniques in situ. Portable X-ray fluorescence and Fourier-transform total reflection infrared spectroscopy complemented the use of visible and ultraviolet light photography to get an overview and specific information on the vase. The XRF data were used to produce false colour maps showing the location of the various elements detected, using the program SmART_scan. The use of gypsum as the material for the white ground is an important result that deserves to be further investigated in similar vases.