Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest; however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report the structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site. We demonstrate that their incorporation in bifunctional degraders induces targeted protein degradation of BRD4 or the androgen receptor without further linker optimization. Our study discloses the first covalent VHL ligands which can be implemented directly in bifunctional degrader design, expanding the substrate scope of covalent E3 ligase PROTACs

Early development of spasticity following stroke: a prospective, observational trial

This study followed a cohort of 103 patients at median 6 days, 6 and 16 weeks after stroke and recorded muscle tone, pain, paresis, Barthel Index and quality of life score (EQ-5D) to identify risk-factors for development of spasticity. 24.5% of stroke victims developed an increase of muscle tone within 2 weeks after stroke. Patients with spasticity had significantly higher incidences of pain and nursing home placement and lower Barthel and EQ-5D scores than patients with normal muscle tone. Early predictive factors for presence of severe spasticity [modified Ashworth scale score (MAS) ≥3] at final follow-up were moderate increase in muscle tone at baseline and/or first follow-up (MAS = 2), low Barthel Index at baseline, hemispasticity, involvement of more than two joints at first follow-up, and paresis at any assessment point. The study helps to identify patients at highest risk for permanent and severe spasticity, and advocates for early treatment in this group