Browsing by Subject "PROTEIN-PROTEIN INTERACTIONS"

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  • Välimäki, Mika J.; Tölli, Maria A.; Kinnunen, Sini M.; Aro, Jani; Serpi, Raisa; Pohjolainen, Lotta; Talman, Virpi; Poso, Antti; Ruskoaho, Heikki J. (2017)
    Transcription factors are pivotal regulators of gene transcription, and many diseases are associated with the deregulation of transcriptional networks. In the heart, the transcription factors GATA4 and NKX2-5 are required for cardiogenesis. GATA4 and NKX2-5 interact physically, and the activation of GATA4, in cooperation with NKX2-5, is essential for stretch-induced cardiomyocyte hypertrophy. Here, we report the identification of four small molecule families that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. A fragment-based screening, reporter gene assay, and pharmacophore search were utilized for the small molecule screening, identification, and optimization. The compounds modulated the hypertrophic agonist-induced cardiac gene expression. The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide (3, IC50 = 3 mu M), exhibited no activity on the protein kinases involved in the regulation of GATA4 phosphorylation. The identified and chemically and biologically characterized active compound, and its derivatives may provide a novel class of small molecules for modulating heart regeneration.
  • Souza, Paulo C. T.; Alessandri, Riccardo; Barnoud, Jonathan; Thallmair, Sebastian; Faustino, Ignacio; Grunewald, Fabian; Patmanidis, Ilias; Abdizadeh, Haleh; Bruininks, Bart M. H.; Wassenaar, Tsjerk A.; Kroon, Peter C.; Melcr, Josef; Nieto, Vincent; Corradi, Valentina; Khan, Hanif M.; Domanski, Jan; Javanainen, Matti; Martinez-Seara, Hector; Reuter, Nathalie; Best, Robert B.; Vattulainen, Ilpo; Monticelli, Luca; Periole, Xavier; Tieleman, D. Peter; de Vries, Alex H.; Marrink, Siewert J. (2021)
    The coarse-grained Martini force field is widely used in biomolecular simulations. Here we present the refined model, Martini 3 (http://cgmartini.nl), with an improved interaction balance, new bead types and expanded ability to include specific interactions representing, for example, hydrogen bonding and electronic polarizability. The updated model allows more accurate predictions of molecular packing and interactions in general, which is exemplified with a vast and diverse set of applications, ranging from oil/water partitioning and miscibility data to complex molecular systems, involving protein-protein and protein-lipid interactions and material science applications as ionic liquids and aedamers.
  • Tonali, Nicolo; Hericks, Loreen; Schroeder, David C.; Kracker, Oliver; Krzemieniecki, Radoslaw; Kaffy, Julia; Le Joncour, Vadim; Laakkonen, Pirjo; Marion, Antoine; Ongeri, Sandrine; Dodero, Veronica I.; Sewald, Norbert (2021)
    In peptidotriazolamers every second peptide bond is replaced by a 1H-1,2,3-triazole. Such foldamers are expected to bridge the gap in molecular weight between small-molecule drugs and protein-based drugs. Amyloid beta (A beta) aggregates play an important role in Alzheimer's disease. We studied the impact of amide bond replacements by 1,4-disubstituted 1H-1,2,3-triazoles on the inhibitory activity of the aggregation "hot spots" (KLVFF20)-L-16 and G(39)VVIA(42) in A beta(1-42). We found that peptidotriazolamers act as modulators of the A beta(1-42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early A beta oligomers, depending on the position of the triazoles, which is also supported by computational studies. Preliminary in vitro results demonstrate that a highly active peptidotriazolamer is also able to cross the blood-brain-barrier.
  • Mäkelä, Noora; Brinck, Outi; Sontag-Strohm, Tuula (2020)
    The physiological functionality of cereal beta-glucan (beta-glucan) has been mainly attributed to its ability to form viscous solutions in the gastrointestinal (GI) tract. The viscosity is dependent on the concentration, extractability and molecular weight of beta-glucan, and to enable maximal functionality, these factors should therefore be acknowledged and their role in the physiological functionality of cereal beta-glucan further studied. An in vitro GI simulation with separate oral, gastric and small intestine phases was used to model the state of beta-glucan from various oat products in the GI tract. A rather large variation (from 26% to 99%) was observed in the extractabilities between product categories, with the highest extractabilities observed in spoonable products. The viscosities also varied highly within categories. When the comparison was done at similar concentration levels, the highest viscosities were observed in the products produced through dry processes, and moisture content during processing was suggested to be essential to the extent of beta-glucan degradation. The viscosity in samples that were likely to exhibit enzymatic activity was shown to be rather low, and thus the physiological functionality of beta-glucan may be threatened if the product also contains grain ingredients other than kiln-dried oat. Clear differences were observed in the functionality of beta-glucan in the GI tract model depending on a product type, and these were explained by differences in ingredients and processes. However, further studies are needed to specify the influence of each factor and to clarify the factors determining the physiological functionality of beta-glucan in food products.