Membrane Permeant Analogs for Independent Cellular Introduction of the Terpene Precursors Isopentenyl- and Dimethylallyl-Pyrophosphate.

Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are the central five-carbon precursors to all terpenes. Despite their significance, exogenous, independent delivery of IPP and DMAPP to cells is impossible as the negatively charged pyrophosphate makes these molecules membrane impermeant. Herein, we demonstrate a facile method to circumvent this challenge through esterification of the ß-phosphate with two self-immolative esters (SIEs) that neutralize the negatively charged pyrophosphate to yield membrane-permeant analogs of IPP and DMAPP. Following cellular incorporation, general esterase activity initiates cleavage of the SIEs, resulting in traceless release of IPP and DMAPP for metabolic utilization. Addition of the synthesized IPP and DMAPP precursor analogs rescued cell growth of glioblastoma (U-87MG) cancer cells concurrently treated with the HMG-CoA reductase inhibitor pitavastatin, which otherwise abrogates cell growth via blocking production of IPP and DMAPP. This work demonstrates a new application of a prodrug strategy to incorporate a metabolic intermediate and promises to enable future interrogation of the distinct biological roles of IPP and DMAPP.

Management of Hepatitis C in Delaware Prisons: : Approaching Microenvironmental Eradication.

The management of chronic hepatitis C virus (HCV) infection has been transformed due to the arrival of HCV-specific Direct-Acting Antivirals (DAAs), which are safer, more effective, and better tolerated than the interferon-based therapies that preceded them. Compared with community healthcare systems, many prison healthcare systems have been slower to adopt the routine use of HCV DAAs despite the fact that HCV infection disproportionately affects individuals in correctional institutions. In 2015, the Delaware Department of Correction (DDOC) launched a treatment program that prioritized treatment for patients who were at greatest risk of disease complications. To date, 327/345 (95%) of eligible current HCV patients have initiated DAA therapy. A total of 196/199 (98.4%) patients who have initiated treatment and who have post-treatment data available have achieved sustained virologic response, defined as undetectable HCV viral load 12 weeks after treatment. Applying a concept of microenvironmental eradication, it can reasonably be concluded that that DDOC is approaching this benchmark with regard to chronic HCV infection and will soon enter a "maintenance phase," during which it will be feasible to treat new cases of HCV in real time. Correctional systems with significant numbers of untreated hepatitis C patients may want to consider implementing HCV treatment programs that focus on cost-effectiveness and prioritize treatment for patients who are at greatest risk of disease complications.

Transcription factor logic using chemical complementation.

Chemical complementation was used to make a transcription factor circuit capable of performing complex Boolean logic.