American Chemical Society
Central Ohio Valley Section
The B-cell lymphoma 2 (Bcl2) proteins are a family of intrinsic apoptosis regulators that control outer mitochondrial membrane permeabilization. Anti-apoptotic Bcl2 proteins exert their biological effects by sequestering pro-apoptotic Bcl2 members on the surface of mitochondria, inhibiting the release of cytochrome c. Anti-apoptotic Bcl2 proteins have been implicated in pathogenic cell survival and have attracted considerable interest as therapeutic targets. Despite intense effort, however, the development of molecules that selectively inhibit anti-apoptotic Bcl2 proteins remains a pressing challenge. In an attempt to develop selective inhibitors of anti-apoptotic Bcl2 proteins, we have grafted residues of the helical BH3 interaction domains of the pro-apoptotic Bcl2 proteins Bax and Bak critical for anti-apoptotic Bcl2 inhibition to the a-helix of the small protein scyllatoxin (ScTx). We then screened this class of ScTx-based mimetics against anti-apoptotic Bcl-2 in vitro. Through these experiments, we show that the specific BH3 sequence grafted to ScTx is important for imparting selectivity, as ScTx-Bax mimetics bind Bcl-2 with almost four-times greater affinity than ScTx-Bak. These results indicate that the interplay between primary sequence and spatial fixation is crucial for selective Bcl-2 recognition. We anticipate that these ‘synthetic biologics’ will facilitate the development of highly specific protein-based inhibitors of Bcl-2 function and will support investigations into the molecular mode of action of proteins in the Bcl2 family.
Justin Holub earned a BS in Biochemistry from Rider University (Lawrenceville, NJ) in 2001 working with the late Professor Bruce Burnham. While an undergrad, he developed a series of highly functionalized pyrrole derivatives that were found to be potent hypolipidemic agents in rats. Following completion of his undergraduate degree, Justin went on to study radiobiology at Memorial Sloan-Kettering Cancer Center in New York City. There he worked under the guidance of Professor Joanne Weidhaas mapping radio-protective pathways in C. elegans. He then went on to pursue his Ph.D. at New York University under the tutelage of Professor Kent Kirshenbaum, where he worked on developing highly specific bioconjugation reactions to functionalize peptidomimetic oligomers. After completion of his Ph.D. in 2009, Justin pursued his postdoctoral studies at Yale University, working with Alanna Schepartz to develop cationic miniature proteins as tools to study endosomal trafficking in live cells.
Dr. Holub joined the faculty of Ohio University in the Fall of 2013. At OU, Professor Holub teaches undergraduate courses in General Biochemistry and graduate courses in Chemical Biology and Advanced Cell Biology. Professor Holub’s research program focuses on the development of chemical tools to investigate biological processes. More specifically, his lab uses multidisciplinary approaches to design and develop non-natural molecules, such as synthetic biologics and profluorescent ligands, for studying and modulating therapeutically relevant protein-protein interactions.
Dr. Holub's currnent CV can be found by clicking here.
E-mail Notification of Meetings
A Request from the Newsletter Editor/Webmaster:
What do you think of this as a replacement for the newsletter? Comments and suggestions are always welcome. Please send any and all ideas for improvement to me at email@example.com. Volunteers who would be interested in working on the web site are always welcomed.