Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase.

Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD⁺/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors.

A light-driven anti-cancer dual-therapeutic cassette enhances solid tumour regression.

The majority of anticancer therapeutics have failed to control the target cancers. Thus, new rational design concepts are critical. In most of the biological reactions, a cascade pathway is used to activate appropriate responses. In the cascade pathway, a small signal derived from neighboring environments can be amplified and it further triggers overwhelming and specialized responses. It can be applied to achieve powerful therapeutic effects for novel drug design strategies. Inspired by this concept, we design a preferential dual anti-cancer therapeutic cassette composed of (i) DNA/RNA nanostructures as both anticancer containers and target ligands and (ii) a gold nanocrystal as localized heat inducers. We demonstrate that this multi-modular platform is superior to conventional cancer medications in that it had higher drug loading efficiency, tunable drug release, and intrinsic serum stability characteristics. Both doxorubicin chemotherapy and thermal ablation exert a powerful synergistic killing effect that resulted in prostate cancer regression both in vitro and in vivo. We speculate that our novel anti-cancer drug system can be adapted to effectively destroy many different types of solid cancers.

A specific two-pore domain potassium channel blocker defines the structure of the TASK-1 open pore.

Two-pore domain potassium (K(2P)) channels play a key role in setting the membrane potential of excitable cells. Despite their role as putative targets for drugs and general anesthetics, little is known about the structure and the drug binding site of K(2P) channels. We describe A1899 as a potent and highly selective blocker of the K(2P) channel TASK-1. As A1899 acts as an open-channel blocker and binds to residues forming the wall of the central cavity, the drug was used to further our understanding of the channel pore. Using alanine mutagenesis screens, we have identified residues in both pore loops, the M2 and M4 segments, and the halothane response element to form the drug binding site of TASK-1. Our experimental data were used to validate a K(2P) open-pore homology model of TASK-1, providing structural insights for future rational design of drugs targeting K(2P) channels.