A5021090438- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- SARS-CoV-2 and COVID-19 Research
- Ubiquitin and proteasome pathways
- Antimicrobial Peptides and Activities
- Histone Deacetylase Inhibitors Research
- vaccines and immunoinformatics approaches
- Multiple Myeloma Research and Treatments
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Parkinson's Disease Mechanisms and Treatments
- SARS-CoV-2 detection and testing
- Pharmacological Effects and Toxicity Studies
- Drug Transport and Resistance Mechanisms
- RNA and protein synthesis mechanisms
- Pharmaceutical and Antibiotic Environmental Impacts
- Synthesis and biological activity
University of Bonn
2022-2025
A novel class of USP7 PROTACs were designed and synthesized. CST967, a CRBN-based degrader, showed potent selective depletion leading to apoptosis in multiple cancer lines.
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce degradation of IMiD neosubstrates inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, off-target neosubstrate modulation features to develop novel...
Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series 21 peptidomimetics evaluated their inhibitory activity against human cathepsins L, B, S. Structural diversity was realized by combinations different C-terminal warhead functions N-terminal capping groups, while central Leu-Phe fragment maintained. Several compounds were identified as promising cathepsin L S inhibitors with
The development of von Hippel–Lindau (VHL) hijacking proteolysis-targeting chimeras (PROTACs) has been hindered by suboptimal physicochemical properties, including high total polar surface area (TPSA), hydrogen bond donor (HBD) counts, and poor solubility. This study explores a novel approach to enhance the characteristics VHL-recruiting USP7 degraders while maintaining their efficacy. By systematically optimizing lipophilicity, count, TPSA USP-targeting moieties, we designed series...
Proteolysis-targeting chimeras (PROTACs) are emerging new therapeutic modalities that facilitate the targeted degradation of disease-relevant proteins via an event-driven mode action. In this work, we report design, synthesis, and biological evaluation first-in-class selective degraders class IIb histone deacetylases (HDACs) 6 10. To end, dual HDAC6/10 inhibitor tubastatin A a ring-opened analog were connected well-established PROTAC linkers to pomalidomide phenylglutarimides as cereblon...
Given the crucial role of main protease (M
Introduction of fluorine into bioactive molecules has attracted much attention in drug development. For example, tetrafluorination the phthalimide moiety immunomodulatory drugs (IMiDs) a strong beneficial effect on ability to inhibit angiogenesis. The neomorphic activity E3 ligase complexes is induced by binding IMiDs cereblon. We investigated that set eight thalidomide analogs, comprising non- and tetrafluorinated counterparts, did not induce degradation substrates (IKZF3, GSPT1, CK1α,...
Proteolysis-targeting chimeras (PROTACs) are emerging new therapeutic modalities that facilitate the targeted degradation of disease-relevant proteins via an event-driven mode action. In this work, we report design, synthesis, and biological evaluation first-in-class selective degraders class IIb histone deacetylases (HDACs) 6 10. To end, dual HDAC6/10 inhibitor Tubastatin A a ring-opened analog were connected well-established PROTAC linkers to pomalidomide phenylglutarimides as cereblon...
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide represent the most typical cereblon (CRBN) recruiters that are frequently utilized in proteolysis-targeting chimera (PROTAC) design. These CRBN binders, however, cause degradation of IMiD neosubstrates innately unstable they undergo hydrolytic under mild conditions. Here we present systematic approach towards novel non-phthalimide binders were obtained via simultaneous optimization their physiochemical...
A titrant for the SARS-CoV-2 main protease (Mpro) was developed that enables, first time, exact determination of concentration enzymatically active Mpro by active-site titration. The covalent binding mode tetrapeptidic elucidated crystal structure enzyme-titrant complex. Four fluorogenic substrates Mpro, including a prototypical, internally quenched Dabcyl-EDANS peptide, were compared in terms solubility under typical assay conditions. By exploiting new titrant, key kinetic parameters...
Proteolysis-targeting chimeras (PROTACs) are emerging new therapeutic modalities that facilitate the targeted degradation of disease-relevant proteins via an event-driven mode action. In this work, we report design, synthesis, and biological evaluation first-in-class selective degraders class IIb histone deacetylases (HDACs) 6 10. To end, dual HDAC6/10 inhibitor Tubastatin A a ring-opened analog were connected well-established PROTAC linkers to pomalidomide phenylglutarimides as cereblon...
Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series 21 peptidomimetics evaluated their inhibitory activity against human cathepsins L, B, S. Structural diversity was realized by combinations different C-terminal warhead functions N-terminal capping groups, while central Leu-Phe fragment maintained. Several compounds were identified as promising cathepsin L S inhibitors with Ki values in low nanomolar...