Humanized Candida and NanoBiT Assays Expedite Discovery of Bdf1 Bromodomain Inhibitors With Antifungal Potential.

The fungal Bromodomain and Extra-Terminal (BET) protein Bdf1 is a potential antifungal target against invasive fungal infections. However, the need to selectively inhibit both Bdf1 bromodomains (BDs) over human orthologs and the lack of molecular tools to assess on-target antifungal efficacy hamper efforts to develop Bdf1 BD inhibitors as antifungal therapeutics. This study reports a phenyltriazine compound that inhibits both Bdf1 BDs from the human fungal pathogen Candida glabrata with selectivity over the orthologous BDs from the human BET protein Brd4.

Oral USC-093, a novel homoserinamide analogue of the tyrosinamide (S)-HPMPA prodrug USC-087 has decreased nephrotoxicity while maintaining antiviral efficacy against human adenovirus infection of Syrian hamsters.

Adenovirus infections of immunocompromised humans are a significant source of morbidity and mortality. Presently, there is no drug specifically approved for the treatment of adenovirus infections by the FDA. The state-of-the-art treatment of such infections is the off-label use of cidofovir, an acyclic nucleotide phosphonate.

Microwave-Accelerated McKenna Synthesis of Phosphonic Acids: An Investigation.

Phosphonic acids represent one of the most important categories of organophosphorus compounds, with myriad examples found in chemical biology, medicine, materials, and other domains. Phosphonic acids are rapidly and conveniently prepared from their simple dialkyl esters by silyldealkylation with bromotrimethylsilane (BTMS), followed by desilylation upon contact with water or methanol. Introduced originally by McKenna, the BTMS route to phosphonic acids has long been a favored method due to its convenience, high yields, very mild conditions, and chemoselectivity.

Toward more potent imidazopyridine inhibitors of Candida albicans Bdf1: Modeling the role of structural waters in selective ligand binding.

Novel agents to treat invasive fungal infections are urgently needed because the small number of established targets in pathogenic fungi makes the existing drug repertoire particularly vulnerable to the emergence of resistant strains. Recently, we reported that Candida albicans Bdf1, a bromodomain and extra-terminal domain (BET) bromodomain with paired acetyl-lysine (AcK) binding sites (BD1 and BD2) is essential for fungal cell growth and that an imidazopyridine (1) binds to BD2 with selectivity versus both BD1 and human BET bromodomains. Bromodomain binding pockets contain a conserved array of structural waters.

Anomeric Fatty Acid Functionalization Prevents Nonenzymatic -Glycosylation by Monosaccharide Metabolic Chemical Reporters.

Metabolic chemical reports have fundamentally changed the way researchers study glycosylation. However, when administered as per--acetylated sugars, reporter molecules can participate in nonspecific chemical labeling of cysteine residues termed -glycosylation. Without detailed proteomic analyses, these labeling events can be indistinguishable from bona fide enzymatic labeling convoluting experimental results.