Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.

Milk as a Potential Source of Aeromonas Gastrointestinal Infection.

The incidence and properties of Aeromonas species found in milk were examined to evaluate the potential of milk as a vehicle for the transmission of Aeromonas gastroenteritis. Aeromonads are common in raw milk (60%, 43 of 72 samples, positive). Pasteurization is effective at removing this contamination. Nevertheless, around 4% (seven of 183) pasteurized milk samples contained potentially significant strains, apparently introduced by subsequent handling of the milk. Some of these strains were indistinguishable from diarrhea-associated strains and were able to produce exotoxins at 37°C and adhere to epithelial cells. Adhesive ability and piliation increased when these strains were grown at low temperature. Such strains, although mesophilic, could reach high numbers in refrigerated milk without detectable spoilage of the milk. They pose the risk of colonization and in vivo toxin production. Further studies are required, but ingestion of preformed toxins produced in stored pasteurized milk may be of less concern, as psychrotrophic aeromonads, with the ability to produce large amounts of exotoxins in milk, appear to be uncommon and exotoxin production in milk was significantly lower than in bacteriological medium.