Structural basis for ring-opening fluorescence by the RhoBAST RNA aptamer.

Tagging RNAs with fluorogenic aptamers has enabled imaging of transcripts in living cells, thereby revealing novel aspects of RNA metabolism and dynamics. While a diverse set of fluorogenic aptamers has been developed, a new generation of aptamers are beginning to exploit the ring-opening of spirocyclic rhodamine dyes to achieve robust performance in live mammalian cells. These fluorophores have two chemical states: a colorless, cell-permeable spirocyclic state and a fluorescent zwitterionic state.

Unveiling the promise of peptide nucleic acids as functional linkers for an RNA imaging platform.

Linkers in chemical biology provide more than just connectivity between molecules; their intrinsic properties can be harnessed to enhance the stability and functionality of chemical probes. In this study, we explored the incorporation of a peptide nucleic acid (PNA)-based linker into RNA-targeting probes to improve their affinity and specificity. By integrating a PNA linker into a small molecule probe of the Riboglow platform, we enabled dual binding events: cobalamin (Cbl)-RNA structure-based recognition and sequence-specific PNA-RNA interaction.

Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies.

The COVID-19 pandemic has created a global health crisis, with challenges arising from the ongoing evolution of the SARS-CoV-2 virus, the emergence of new strains, and the long-term effects of COVID-19. Aiming to overcome the development of viral resistance, our study here focused on developing broad-spectrum pan-coronavirus antiviral therapies by targeting host protein quality control mechanisms essential for viral replication. Screening an in-house compound library led to the discovery of three candidate compounds targeting cellular proteostasis.

Structure-Based Design and Development of Phosphine Oxides as a Novel Chemotype for Antibiotics that Dysregulate Bacterial ClpP Proteases.

A series of arylsulfones and heteroarylsulfones have previously been demonstrated to dysregulate the conserved bacterial ClpP protease, causing the unspecific degradation of essential cellular housekeeping proteins and ultimately resulting in cell death. A cocrystal structure of a 2-β-sulfonylamide analog, ACP1-06, with ClpP showed that its 2-pyridyl sulfonyl substituent adopts two orientations in the binding site related through a sulfone bond rotation. From this, a new -aryl phosphine oxide scaffold, designated as ACP6, was designed based on a "conformation merging" approach of the dual orientation of the ACP1-06 sulfone.