Teva Pharmaceuticals Marc A. Goshko Memorial Grant Program Awardees 2009 - 2012

Dr. Alexander Deiters
North Carolina State University

"Discovery and application of small molecule modifiers of microRNA function.

“MicroRNAs are single stranded ribonucleic acid (RNA) molecules of approximately 20 nucleotides that regulate gene expression by specific binding to the 3’ untranslated region of target messenger RNAs, leading to the downregulation of gene expression. It has been estimated that microRNAs are involved in the regulation of up to 30% of all genes in humans. The microRNA miR-122 is the most abundant miRNA in the liver and is necessary for the translation and replication of the hepatitis C virus (HCV). At the Teva Symposium, small molecules capable of specifically inhibiting the activity of miR-122 were presented. These compounds constitute new tools to elucidate the involvement of miR-122 in HCV infection and could potentially be developed into fundamentally new antiviral therapeutic agents. Current studies that involve structure-activity relationship investigations to understand the molecular requirements for the miR-122 inhibitory activity were discussed and steps toward the elucidation of the precise mode of action of the discovered inhibitors were outlined. In addition, initial investigations of the small molecules’ antiviral activity showed the ability to greatly reduce HCV levels in human liver cells.

Discussions with Teva scientists at the symposium provided important insight into additional future directions of the presented inhibition of miR-122 by small molecules.” Dr. Alex Deiters

Dr. Brian Stoltz
California Institute of Technology

"A novel approach to antitumor antibiotics: Using the power of benzyne in synthesis."

"Presenting the progress of “A Novel Approach to Antitumor Antibiotics” at the Teva Award Symposium at the August 2012 ACS meeting in Philadelphia was not only an honor, but made for a highly interesting and diverse afternoon of science. Early achievements from our laboratory in the area include the asymmetric total synthesis of (–)-lemonomycin, and the development of an aryne annulation methodology for the synthesis of isoquinolines, have inspired our application of this method to a concise asymmetric total synthesis of (–)-quinocarcin, a mono-THIQ alkaloid. Our additional work within this program has focused on the application of this and other aryne technologies to the construction of polyfunctionalized bis-isoquinolines en route to several additional, biosynthetically distinct members of the THIQ alkaloids.

The Teva scientists and ACS staff made the experience very pleasant and the attentive audience was highly appreciated. "I thought the whole experience was very enjoyable!" Dr. Brian Stoltz

Dr. Xin Guo
University of the Pacific

"Trans-2-aminocyclohexanol-based lipids as pH-sensitive conformational switches in liposomes for drug delivery."

“It was a great pleasure to present the progress of our TEVA project, “trans‐2‐Aminocyclohexanol-based Lipids as pH‐Sensitive Conformational Switches in Liposomes for Drug Delivery” at the ACS meeting. Over the past three years, we have designed and prepared a variety of trans-2-aminocyclohexanol (TACH) lipids as molecular switches of liposomes. Our NMR, fluorometric and EM studies have demonstrated that the drop of pH triggers the conformational flip of the trans-2-aminocyclohexanol lipids, which in turn destabilizes liposome membranes. For pharmaceutical applications, PEGylated liposomes consisting of the TACH lipids (fliposomes) enhanced the anticancer effect of methotrexate and TACH lipids enhanced the gene transfection of cationic lipoplexes by up to 100-fold in cultured cells.

We enjoyed the presentations of the other TEVA recipients and the discussions with scientists from TEVA and from ACS at the symposium. We thank TEVA and ACS, who supported this exciting project, which opens many doors for the TACH lipids and liposomes to benefit modern medicine.” Dr. Xin Guo