Podcast Episode · Approved · 13 March · 2h 22m

Plasma kallikrein (pKal) is a trypsin-like serine protease involved in the kallikrein-kinin, renin-angiotensin, and complement pathways, making it an attractive target for diseases, such as hereditary angioedema, diabetic mellitus complications, and cerebrovascular disorders. As part of an internal program to develop orally bioavailable small-molecule pKal inhibitors, we report lead optimization efforts within the spirocarbamate scaffold, highlighting a structure-based drug design strategy to engineer hydrogen bond interactions with N-benzyl aminopyrazoles. Additionally, mitigation of time-dependent inhibition (TDI) liability and optimization of the overall profile were achieved through a two-pronged strategy: (1) incorporating increased Fsp3 modifications via N-alkylation and (2) leveraging torsional strain in N-aryl analogs.

🇺🇸 Gate Bioscience: Revolutionary 'molecular gate' drugs that act like cellular bouncers, blocking disease-causing proteins and unlocking groundbreaking treatments for previously untreatable condition...

High-throughput screening (HTS) remains central to small molecule lead discovery, but increasing assay complexity challenges the screening of large compound libraries. While retrospective studies have...

Tool compounds separate pain relief from breathing suppression in mice

In Escherichia coli, elevated levels of free l-tryptophan (l-Trp) promote translational arrest of the TnaC peptide by inhibiting its termination. However, the mechanism by which translation-termination by the UGA-specific decoding release factor 2 (RF2) is inhibited at the UGA stop codon of stalled …

New funding brings total capital raised to $135 million. Molecular gates offer the convenience of a pill with potential for superior efficacy through a novel mechanism that eliminates disease-causing ...

Charles Lieber, the nanoscience pioneer convicted for not disclosing his ties to China, has just joined Tsinghua University

Necessity is the mother of invention. Most synthetic chemistry innovations are driven by our desire to make molecules. In the first half of the 20th century, much of this work was inspired by natural ...

Molecules that can perturb protein-protein interactions have an immense impact on chemical biology and therapeutics. However, such compounds typically rely on accessory proteins to function, such as E...

A gold-catalyzed C(sp3)–C(sp2) Suzuki–Miyaura coupling reaction facilitated by ligand-enabled Au(I)/Au(III) redox catalysis was developed. The cross-coupling of alkyl organometallics was first realiz...

Vitamin C directly modifies lysine residues through vitcylation, regulating STAT1 signaling and enhancing anti-tumor immune responses by preventing STAT1 dephosphorylation.