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Covalent chemical probes and drugs combine unique pharmacologic properties with the availability of straightforward compound profiling technologies via chemoproteomic platforms. These advantages have fostered the development of suitable electrophilic “warheads” for systematic covalent chemical probe discovery. Despite undisputable advances in the last years, the targeted development of proteome-wide selective covalent probes remains a challenge for dipeptidyl peptidase (DPP) 8 and 9 (DPP8/9), intracellular serine hydrolases of the pharmacologically relevant dipeptidyl peptidase 4 activity/structure homologues (DASH) family. Here, we show the exploration of the natural product Sulphostin, a DPP4 inhibitor, as a starting point for DPP8/9 inhibitor development. The generation of Sulphostin-inspired N -phosphonopiperidones leads to derivatives with improved DPP8/9 inhibitory potency, an enhanced proteome-wide selectivity and confirmed DPP8/9 engagement in cells, thereby representing that structural fine-tuning of the warhead’s leaving group may represent a straightforward strategy for achieving target selectivity in exoproteases such as DPPs. The targeted development of proteome-wide selective covalent probes remains a challenge. Here, the authors show the exploration of the natural product Sulphostin as a starting point for dipeptidyl peptidase 8 and 9 inhibitor development.

Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (MGPROTACs) approach that chemically conjugates a molecular glue stabilizer to a VHL-recruiting ligand to capture and ubiquitinate the 14-3-3/Estrogen Receptor α (ERα) complex. Our designed MGPROTACs engage a composite interface between 14-3-3 and the disordered F-domain of ERα, promoting cooperative complex formation and target ubiquitination. Biophysical characterization revealed distinct linker-dependent cooperativities across the MGPROTAC series, which influenced both cellular permeability and ubiquitination efficiency. Cryo-EM of the most cooperative MGPROTAC uncovers de novo VHL–14-3-3ζ contacts, while molecular dynamics simulations rationalize the stabilizing interactions underlying cooperativity. Strikingly, fine-tuning linker design enables selective ubiquitination of distinct complex subunits. These findings establish a structural and mechanistic framework for integrating molecular glue and PROTAC principles, expanding the scope of drug discovery to previously intractable protein complexes.

Objective: The SENTRY antimicrobial surveillance program was established to monitor the occurrence and antimicrobial susceptibility of bacterial pathogens via an international network of sentinel hospitals. Material and Methods: Microorganisms were forwarded to the reference laboratory for testing against various antimicrobial agents using broth microdilution. Twenty European hospitals referred 286 Streptococcus pneumoniae, 309 Haemophilus influenzae, and 167 Moraxella catarrhalis isolates during the first 10 months of the study, starting in April 1997. Results: Seven percent of the S. pneumoniae isolates were highly resistant to penicillin, and 21 % showed intermediate resistance. The highly resistant pneumococcal isolates came from Coimbra, Barcelona, Athens, and London, whereas the intermediate penicillin-resistant isolates were received from all participating countries. The incidence of intermediate penicillin-resistant pneumococci was lowest in Lausanne, Freiburg and Duesseldorf, London, and Utrecht and highest in southern European countries. Fifty-five percent of the penicillin-resistant S. pneumoniae were also resistant to erythromycin, and 35% to clindamycin. Sparfloxacin, trovafloxacin, levofloxacin, and vancomycin were fully active against pneumococcal isolates. Haemophilus influenzae isolates were generally highly susceptible to most of the antibiotics tested, and 92% of the M. catarrhalis isolates were resistant to penicillin. Susceptibility to cephalosporins, ciprofloxacin, levofloxacin, and rifampicin was 100%. Conclusion: Penicillin may no longer be the first-choice drug for empirical treatment of pneumococcal infections. The newer fluoroquinolones may play a role in the empirical treatment of community-acquired pneumonia.