https://hdl.handle.net/20.500.11811/617 Tue, 14 Apr 2026 15:24:02 GMT 2026-04-14T15:24:02Z https://hdl.handle.net/20.500.11811/13551 Structure-affinity and structure-residence time relationships of macrocyclic Gα_q protein inhibitors Voss, Jan H.; Crüsemann, Max; Bartling, Christian R.O.; Kehraus, Stefan; Inoue, Asuka; König, Gabriele M.; Strømgaard, Kristian; Müller, Christa E. The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gα_q/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gα_q protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gα_q protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome. Fri, 21 Apr 2023 00:00:00 GMT https://hdl.handle.net/20.500.11811/13551 2023-04-21T00:00:00Z https://hdl.handle.net/20.500.11811/13301 Biosynthesis of the corallorazines, a widespread class of antibiotic cyclic lipodipeptides Dreckmann, Teresa M.; Fritz, Lisa; Kaiser, Christian F.; Bouhired, Sarah M.; Wirtz, Daniel A.; Rausch, Marvin; Müller, Anna; Schneider, Tanja; König, Gabriele M.; Crüsemann, Max Corallorazines are cyclic lipodipeptide natural products produced by the myxobacterium <em>Corallococcus coralloides</em> B035. To decipher the basis of corallorazine biosynthesis, the corallorazine nonribosomal peptide synthetase (NRPS) biosynthetic gene cluster <em>crz</em> was identified and analyzed in detail. Here, we present a model of corallorazine biosynthesis, supported by bioinformatic analyses and <em>in vitro</em> investigations on the bimodular NRPS synthesizing the corallorazine core. Corallorazine biosynthesis shows several distinct features, such as the presence of a dehydrating condensation domain, and a unique split adenylation domain on two open reading frames. Using an alternative fatty acyl starter unit, the first steps of corallorazine biosynthesis were characterized <em>in vitro</em>, supporting our biosynthetic model. The dehydrating condensation domain was bioinformatically analyzed in detail and compared to other modifying C domains, revealing unreported specific sequence motives for this domain subfamily. Using global bioinformatics analyses, we show that the <em>crz</em> gene cluster family is widespread among bacteria and encodes notable chemical diversity. Corallorazine A displays moderate antimicrobial activity against selected Gram-positive and Gram-negative bacteria. Mode of action studies comprising whole cell analysis and <em>in vitro</em> test systems revealed that corallorazine A inhibits bacterial transcription by targeting the DNA-dependent RNA polymerase. Fri, 16 Aug 2024 00:00:00 GMT https://hdl.handle.net/20.500.11811/13301 2024-08-16T00:00:00Z https://hdl.handle.net/20.500.11811/13108 Mesoporous Silica as an Alternative Vehicle to Overcome Solubility Limitations Becker, Tim; Heitkötter, Jan; Krome, Anna K.; Schiefer, Andrea; Pfarr, Kenneth; Ehrens, Alexandra; Grosse, Miriam; Sandargo, Birthe; Stammberger, Ingo; Stadler, Marc; Hübner, Marc P.; Kehraus, Stefan; Hoerauf, Achim; Wagner, Karl G. Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates. Tue, 12 Mar 2024 00:00:00 GMT https://hdl.handle.net/20.500.11811/13108 2024-03-12T00:00:00Z https://hdl.handle.net/20.500.11811/12817 Development of the first geldanamycin-based HSP90 degraders Wurnig, Silas; Vogt, Melina; Hogenkamp, Julian; Dienstbier, Niklas; Borkhardt, Arndt; Bhatia, Sanil; Hansen, Finn Despite the early clinical promise, adverse events such as acquired resistance and dose-limiting toxicities have barred the widespread use of HSP90 inhibitors as anticancer drugs. A new approach involving proteolysis-targeting chimeras (PROTACs) to degrade the protein instead of inhibiting it may overcome these problems. In this work, we describe the design, synthesis, and evaluation of cereblon-recruiting geldanamycin-based HSP90 degraders based on the PROTAC technology. Our best degrader, 3a, effectively decreased HSP90α and HSP90β levels in cells utilizing the ubiquitin–proteasome pathway. Wed, 28 Jun 2023 00:00:00 GMT https://hdl.handle.net/20.500.11811/12817 2023-06-28T00:00:00Z