Insights into the Interaction Landscape of the EVH1 Domain of Mena.

The Enabled/VASP homology 1 (EVH1) domain is a small module that interacts with proline-rich stretches in its ligands and is found in various signaling and scaffolding proteins. Mena, the mammalian homologue of Ena, is involved in diverse actin-associated events, such as membrane dynamics, bacterial motility, and tumor intravasation and extravasation. Two-dimensional (2D) H-N HSQC NMR was used to study Mena EVH1 binding properties, defining the amino acids involved in ligand recognition for the physiological ligands ActA and PCARE, and a synthetic polyproline-inspired small molecule (hereafter inhibitor ).

Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry.

Seasonal and pandemic-associated influenza strains cause highly contagious viral respiratory infections that can lead to severe illness and excess mortality. Here, we report on the optimization of our small-molecule inhibitor F0045(S) targeting the influenza hemagglutinin (HA) stem with our Sulfur-Fluoride Exchange (SuFEx) click chemistry-based high-throughput medicinal chemistry (HTMC) strategy. A combination of SuFEx- and amide-based lead molecule diversification and structure-guided design led to identification and validation of ultrapotent influenza fusion inhibitors with subnanomolar EC cellular antiviral activity against several influenza A group 1 strains.

Synthesis of sugar enones and their use as powerful synthetic precursors of thiodisaccharides.

Monosaccharide derivatives having a double bond conjugated to a carbonyl (sugar enones or enuloses) are relevant synthetic tools. They are also suitable starting materials, or versatile intermediates, for the synthesis of a wide variety of natural or synthetic compounds with a broad spectrum of biological and pharmacological activities. The preparation of enones is mainly focused on the search for more efficient and diastereoselective synthetic methodologies.

Synthesis of thiodisaccharides related to 4-thiolactose. Specific structural modifications increase the inhibitory activity against β-galactosidase.

In the search for new glycosidase inhibitors, a set of benzyl β-D-Gal--(1→4)-3-deoxy-4-thio-α-D-hexopyranosides was synthesized. Diverse configurations were installed at C-2 and C-4 of the glucose residue. The benzyl glycosidic group was kept intact or substituted by an electron-donating or electron-withdrawing group that could also participate in hydrogen bonding.

Synthesis of enantiomerically pure enones (2-benzyloxypyran-3-ones) derived from pentoses.

The useful synthons sugar enones (2-benzyloxypyran-3-ones) derived from pentoses have been prepared starting from 2-acetoxyglycals or benzyl pentopyranosides. The glycals were glycosylated with benzyl alcohol in the presence of a Lewis acid (SnCl or InCl) to give enantioenriched enones (ee = 80-90%). Under catalysis with InCl, benzyl 2-enopyranosides gave also the enones (ee = 87%).

Design and Synthesis of 2-Acetamido-2,3-dideoxythiodisaccharides via Diastereoselective Conjugate Addition to Sugar Enone O-Acetyl Oximes. Galactosidase Inhibition Studies.

The key step in a new synthesis of 2-acetamido-2,3-dideoxy-(1→4)-thiodisaccharides was the conjugate addition of a 1-thiogalactose derivative to E and Z acetyl oximes derived from sugar enones. This reaction was shown to be completely diastereoselective for both the formation of the thioglycosidic linkage and the configuration of acetyl oxime. The thiodisaccharides have been designed as inhibitors of the β-galactosidase from E.