@article{SchulteSoldaSpaenigetal.2022,
  author    = {Schulte, Clemens and Sold{\`a}, Alice and Sp{\"a}nig, Sebastian and Adams, Nathan and Bekić, Ivana and Streicher, Werner and Heider, Dominik and Strasser, Ralf and Maric, Hans Michael},
  title     = {Multivalent binding kinetics resolved by fluorescence proximity sensing},
  series = {Communications Biology},
  volume    = {5},
  journal   = {Communications Biology},
  doi       = {10.1038/s42003-022-03997-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301157},
  year      = {2022},
  abstract  = {Multivalent protein interactors are an attractive modality for probing protein function and exploring novel pharmaceutical strategies. The throughput and precision of state-of-the-art methodologies and workflows for the effective development of multivalent binders is currently limited by surface immobilization, fluorescent labelling and sample consumption. Using the gephyrin protein, the master regulator of the inhibitory synapse, as benchmark, we exemplify the application of Fluorescence proximity sensing (FPS) for the systematic kinetic and thermodynamic optimization of multivalent peptide architectures. High throughput synthesis of +100 peptides with varying combinatorial dimeric, tetrameric, and octameric architectures combined with direct FPS measurements resolved on-rates, off-rates, and dissociation constants with high accuracy and low sample consumption compared to three complementary technologies. The dataset and its machine learning-based analysis deciphered the relationship of specific architectural features and binding kinetics and thereby identified binders with unprecedented protein inhibition capacity; thus, highlighting the value of FPS for the rational engineering of multivalent inhibitors.},
  language  = {en}
}
@article{NishidaXavierdaSilvaSchulteNunesAlvesetal.2023,
  author    = {Nishida Xavier da Silva, Thamara and Schulte, Clemens and Nunes Alves, Ariane and Maric, Hans Michael and Friedmann Angeli, Jos{\´e} Pedro},
  title     = {Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules},
  series = {Cell Death \& Disease},
  volume    = {14},
  journal   = {Cell Death \& Disease},
  doi       = {10.1038/s41419-023-05787-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357943},
  year      = {2023},
  abstract  = {Ferroptosis is a form of cell death characterized by phospholipid peroxidation, where numerous studies have suggested that the induction of ferroptosis is a therapeutic strategy to target therapy refractory cancer entities. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone reductase, is a key determinant of ferroptosis vulnerability, and its pharmacological inhibition was shown to strongly sensitize cancer cells to ferroptosis. A first generation of FSP1 inhibitors, exemplified by the small molecule iFSP1, has been reported; however, the molecular mechanisms underlying inhibition have not been characterized in detail. In this study, we explore the species-specific inhibition of iFSP1 on the human isoform to gain insights into its mechanism of action. Using a combination of cellular, biochemical, and computational methods, we establish a critical contribution of a species-specific aromatic architecture that is essential for target engagement. The results described here provide valuable insights for the rational development of second-generation FSP1 inhibitors combined with a tracer for screening the druggable pocket. In addition, we pose a cautionary notice for using iFSP1 in animal models, specifically murine models.},
  language  = {en}
}