A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A.

Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay.

Utilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A.

Ethnopharmacological Relevance: Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest.

Tripodal transmembrane transporters for bicarbonate.

Easy-to-make tripodal tris-thiourea receptors based upon tris(2-aminoethyl)amine are capable of chloride/bicarbonate transport and as such represent a new class of bicarbonate transport agent.

Ceramide-mediated transport of chloride and bicarbonate across phospholipid membranes.

The sphingolipid, ceramide 1, facilitates transport of Cl(-) and HCO(3)(-) anions across lipid bilayers under conditions where large transmembrane pores are not formed. Ceramide's 1,3-diol unit is essential for both binding and transporting these anions.

Stabilizing guanosine-sterol ion channels with a carbamate to urea modification in the linker.

The use of a bis-urea lithocholamide linker within a guanosine-sterol dimer resulted in formation of large and stable ion channels. The channels were longer-lived than those formed by the corresponding bis-carbamate.

A unimolecular G-quadruplex that functions as a synthetic transmembrane Na+ transporter.

We describe the covalent post-modification of a hydrogen-bonded assembly with the subsequent formation of a potent transmembrane Na+ ion transporter. Olefin metathesis is used to cross-link all 16 guanosine subunits in a lipophilic G-quadruplex. The resulting unimolecular G-quadruplex folds in the environment of a phospholipid membrane and functions as a Na+ ion transporter as judged by fluorescence and 23Na NMR transport assays.