Difference: ParamjitArora (3 vs. 4)

Abstract: DESCRIPTION (provided by applicant): Cellular function depends on highly specific interactions between biomolecules {proteins, RNA, DMA, and carbohydrates). Alpha-helices, ubiquitous elements of protein structures, play fundamental roles in many of these interactions. Alpha-helix mimetics that can predictably disrupt these interactions would be invaluable tools in molecular biology, and potential leads in drug development. A limitation of existing methods for helix stabilization is that they sacrifice side chain functionality to create crosslinks and nucleate helical conformations. Modifying side chains makes them unavailable for molecular recognition and blocks at least one face of the putative helix. We have succeeded in creating a general approach for the synthesis of short stable alpha helices that allows strict preservation of the helix surfaces. Our strategy involves replacement of one of the main chain hydrogen bonds in the target alpha-helix with a covalent bond. The internal placement of the crosslink makes it possible to take advantage of the full helix functionality for molecular recognition. In preliminary studies, we have demonstrated that this new method results in unusually stable artificial alpha-helices. In this application, we explore the utility of these artificial helices for recognition of specific protein pockets and DNA major grooves. With regards to specific aims, (1) we will determine whether replacement of a main chain hydrogen bond in a putative helix with a carbon-carbon bond continually results in highly stable and helical peptides. (2) We will prepare artificial helices that target model (RNase S and GCN4) and therapeutically important protein-protein interactions (HIV-1 gp41) to assess the biological efficacy of these compounds. (3) We will initiate research efforts to develop a new class of sequence-specific DNA binding molecules. Combined these three aims will validate a new approach for the preparation of artificial alpha-helices and their potential use in biomolecular recognition.

Public Health Relevance: This Public Health Relevance is not available.

Institution: NEW YORK UNIVERSITY OFFICE OF SPONSORED PROGRAMS NEW YORK, NY 100122331 Fiscal Year: 2009 Department: CHEMISTRY Project Start: 01-MAR-2005 Project End: 28-FEB-2010 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: BNP

Abstract: DESCRIPTION (provided by applicant): Angiogenesis, the programmed growth blood vessels, is tightly controlled by a number of specific mitogenic factors, among which vascular endothelial growth factor (VEGF) and its receptors play a central role. The levels of VEGF are up-regulated across a broad range of tumors and are involved in key aspects of cancer biology. A hallmark of many cancers, chronic hypoxia, in conjunction with activation of certain oncogenic signaling pathways, is responsible for the elevated levels of VEGF and is associated with invasion and altered energy metabolism. Because tight control of hypoxia-inducible gene expression is critical for cellular existence, the goal of primary importance has been to develop methods of controlling hypoxia-inducible genes in malignant cells while leaving normal cells unaffected. To address this goal, we seek to uncover synthetic molecules that specifically regulate hypoxia-inducible transcription. We hypothesize that the process of transcription could be effectively modulated via disruption of key transcription factor-coactivator interactions involving CH1 domain of protein p300 or the homologous CBP and the C-terminal transactivation domain (C-TAD) of the hypoxia-inducible factor 1(. This complex features short (-helical domains at the interface and suggests that synthetic mimics of these helices would modulate the protein-protein interaction. In this application, we utilize a new class of artificial (-helices with secondary structure that mimics the biologically relevant fragment of HIF-1( C-TAD. In preliminary studies, we have shown that disruption of the Hif-1(/p300 interaction with our synthetic helices results in rapid downregulation of important in cancer progression hypoxia-inducible genes, including VEGF, in cell culture. Our specific aims are to: (1) to design and synthesize artificial helices as inhibitors of the transcription factor-coactivator complex; (2) evaluate binding thermodynamics of each inhibitor toward their protein targets, test their ability to inhibit the cognate protein-protein interaction in vitro, and (3) test the ability artificial helices to disrupt transcription of HIF-inducible genes in cancer and explore the mechanistic details of this disruption at the molecular level. Combined these three aims will validate our hypothesis and create a foundation for the development of a new class of structure and mechanism-based cancer therapeutics. PUBLIC HEALTH RELEVANCE The sequencing of the human genome and recent advances in proteomics have led to a better understanding of the relationship between genetic content and disease. As a result, the development of novel therapies based on controlling gene expression in diseased cells has become an increasingly important goal. By combining the art of chemical synthesis with the methods of molecular biology and genetics, we aim to uncover uniquely specific small molecules that act as suppressors of hypoxia-inducible transcription in cancer with the long-term goal of developing new therapeutics for treatment of aerobic glycolysis and angiogenesis.

Public Health Relevance: The sequencing of the human genome and recent advances in proteomics have led to a better understanding of the relationship between genetic content and disease. As a result, the development of novel therapies based on controlling gene expression in diseased cells has become an increasingly important goal. By combining the art of chemical synthesis with the methods of molecular biology and genetics, we aim to uncover uniquely specific small molecules that act as suppressors of hypoxia-inducible transcription in cancer with the long-term goal of developing new therapeutics for treatment of aerobic glycolysis and angiogenesis.

Thesaurus Terms:

There are no thesaurus terms on file for this project.

Institution: NEW YORK UNIVERSITY OFFICE OF SPONSORED PROGRAMS NEW YORK, NY 100122331 Fiscal Year: 2009 Department: CHEMISTRY Project Start: 01-DEC-2008 Project End: 30-NOV-2010 ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE IRG: CSRS