Inhibitor Mediated Protein Degradation

SummaryThe discovery of drugs that cause the degradation of their target proteins has been largely serendipitous. Here we report that the tert-butyl carbamate-protected arginine (Boc3Arg) moiety provides a general strategy for the design of degradation-inducing inhibitors. The covalent inactivators ethacrynic acid and thiobenzofurazan cause the specific degradation of glutathione-S-transferase when linked to Boc3Arg. Similarly, the degradation of dihydrofolate reductase is induced when cells are treated with the noncovalent inhibitor trimethoprim linked to Boc3Arg. Degradation is rapid and robust, with 30%–80% of these abundant target proteins consumed within 1.3–5 hr. The proteasome is required for Boc3Arg-mediated degradation, but ATP is not necessary and the ubiquitin pathways do not appear to be involved. These results suggest that the Boc3Arg moiety may provide a general strategy to construct inhibitors that induce targeted protein degradation

Evaluation of the humidification requirements of new proton exchange membranes for fuel cells

Measurements of PEM fuel cell device performance were made with different gas inlet temperatures and relative humidity using a newly-designed test fixture. Significant improvement in device performance was observed when the fuel inlet temperature was increased above the operating temperature of the cell. These measurements were then correlated to a model to describe energy and mass transport processes. Proton exchange membrane (PEM), fuel cells--the focus of this study--use an ion conducting polymer, especially polyperfluorosulfonic acid materials. These polymer materials, when imbibed with water, exhibit solution-like properties, but because the anions are chemically bound to the polymeric structure, the electrolyte is contained. Importantly, product water removal is simplified, as electrolyte dilution is not a concern. However, the proton transport rate is a function of the polymer geometry, which is set, in part, by the polymer water content. Consequently, dynamics of water flow are essential to understand the design of efficient conversion devices

PEM (Proton exchange membrane) fuel cell stack heat and mass measurement

PEM stacks are under evaluation as candidates for future space power technology. Results of long-term operation on a set of contemporary stacks fitted with different proton exchange membrane materials are given. Data on water balances show effects of membrane materials on stack performance. 15 refs

An investigation of dual-mode operation of a nuclear-thermal rocket engine

A preliminary assessment of the technical feasibility and mass competitiveness of a dual-mode nuclear propulsion and power system based on Rover-type reactors has been completed. Earlier studies have indicated that dual-mode systems appear attractive for electrical power levels of a few kilowatts. However, at the megawatt electrical power level considered in this study, it appears that extensive modifications to the nuclear-thermal engines would be required, the feasibility of which is unclear. Mass competitiveness at high electrical power levels is also uncertain. Further study of reactor and shield design in conjuction with mission and vehicle studies is necessary in order to determine a useful dual-mode power range. 9 refs., 20 figs., 4 tabs

Boc₃Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome

Targeted protein degradation is a promising strategy for drug design and functional assessment. Several small molecule approaches have been developed that localize target proteins to ubiquitin ligases, inducing ubiquitination and subsequent degradation by the 26S proteasome. We discovered that the degradation of a target protein can also be induced by a recognition ligand linked to <i>tert</i>-butyl carbamate (Boc₃)-protected arginine (B₃A). Here, we show that this process requires the proteasome but does not involve ubiquitination of the target protein. B₃A does not perturb the structure of the target protein; instead, a B₃A-ligand stabilizes its target protein. B₃A ligands stimulate activity of purified 20S proteasome, demonstrating that the tag binds directly to the 20S proteasome. Moreover, purified 20S proteasome is sufficient to degrade target proteins in the presence of their respective B₃A-linked recognition ligands. These observations suggest a simple model for B₃A-mediated degradation wherein the B₃A tag localizes target proteins directly to the 20S proteasome. Thus, B₃A ligands are the first example of a ubiquitin-free strategy for targeted protein degradation

Adolescents' and parents' experiences of managing the psychosocial impact of appearance change during cancer treatment

Using combined qualitative data from multiple case study interviews and an online survey, this study explored the impact of appearance change on 22 adolescents receiving cancer treatment aged 13 to 18 years and six of their parents. Data were analyzed using template analysis. Appearance changes were a major concern. Adolescents typically struggled to adapt to new experiences and concerns related to this highly sensitive issue. Many felt anxious and self-conscious and were reluctant to reveal appearance changes in public. These feelings were compounded by the negative reactions of others (e.g., staring, teasing, and inappropriate questioning), which sometimes lead to avoidance of social activity and threats of noncompliance. Parents of these children felt ill-prepared to manage appearance-related anxieties. Adolescents wanted support to develop the practical and social skills necessary to maintain a "normal" appearance and manage the negative responses of others. However, some adolescents showed resilience and, with support from friends and family, developed strategies to manage their altered appearance and its social consequences. These strategies are explored, which can inform interventions to support adolescents and parents. © 2010 by Association of Pediatric Hematology/Oncology Nurses