Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics.

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads.

Identification of small-molecule binding sites of a ubiquitin-conjugating enzyme-UBE2T through fragment-based screening.

UBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin-conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug-like small molecules. Here, we performed fragment screening using F-nuclear magnetic resonance (NMR) and validated the hits with H- N-heteronuclear single quantum coherence (HSQC) experiment and X-ray crystallographic studies.

Identification and characterization of inhibitors covalently modifying catalytic cysteine of UBE2T and blocking ubiquitin transfer.

UBE2T is an E2 ubiquitin ligase critical for ubiquitination of substrate and plays important roles in many diseases. Despite the important function, UBE2T is considered as an undruggable target due to lack of a pocket for binding to small molecules with satisfied properties for clinical applications. To develop potent and specific UBE2T inhibitors, we adopted a high-throughput screening assay and two compounds-ETC-6152 and ETC-9004 containing a sulfone tetrazole scaffold were identified.

A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir.

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease.

Copper-catalysed synthesis of alkylidene 2-pyrrolinone derivatives from the combination of α-keto amides and alkynes.

A Cu(i)-catalysed addition and cyclisation sequence has been developed for the synthesis of (E)-alkylidene pyrrolinone derivatives. The reactions incorporate simple α-keto amides and alkynes as substrates, and employ a commercially available Cu(i) catalyst. The process tolerates good variation of both starting materials, and delivers the desired pyrrolinones in good yields, with high levels of stereocontrol.

Regioselective copper-catalyzed carboxylation of allylboronates with carbon dioxide.

In the presence of a Cu(I)/NHC catalyst, the reactions of allylboronic pinacol esters with CO2 (1 atm) are highly regioselective, giving exclusively the more substituted β,γ-unsaturated carboxylic acids in most cases. A diverse array of substituted carboxylic acids can be prepared via this method, including compounds featuring all-carbon quaternary centers.