Efforts are focused on the design, synthesis and evaluation of polypeptides and conformationally constrained peptidomimetics that are targeted to inhibit, or otherwise modulate key cellular signal transduction processes. Our goal is to develop therapeutic agents that are selective in inhibiting the oncogenic cell proliferative signal. In the past year we have focused on the research area concerned with developing inhibitors of the ras oncogenic signaling pathway at the c-erbB2 growth factor receptor interaction site with the Grb2 adaptor protein. The Grb2 protein, in its association with ErbB2 and the Sos protein, provides an important link in the cellular proliferative signaling. Based on our previously identified phage library derived cyclic peptide, we developed several analogs that bound selectively to the Grb2-SH2 domain protein at high nanomolar concentrations. Significantly, these agents inhibited the growth factor receptor association with the Grb2 protein in cell homogenates of breast cancer cells. Cell permeabilized analogs also inhibited these multi-protein interactions in breast cancer cells in culture at 2 microM concentrations. These novel inhibitors are non-phosphorylated and do not contain phosphate mimicking groups, and are expected to be constitutively active in cells. Inactivation of the c-erbB2 receptor initiated signaling has potential therapeutic applications, most notably in the management of breast cancer. Work is in progress to modify our active agents to have better transport properties. Good progress has been made in several related project areas. These include: 1./ Development of Matriptase inhibitors. Matriptase was isolated by our collaborators at the Lombardi Cancer Center, GUMC. It is a serine protease that was isolated from human breast cancer cells in culture. It may function to degrade the extracellular matrix, as well as to activate regulatory proteins, such as hepatocyte growth factor (HGF). Development of Matriptase inhibitors may inhibit cell proliferation and cell motility. We have synthesized a bicyclic, highly rigid Matriptase inhibitor that is effective at the 0.9 nanoM level in enzyme assays. This agent, and its molecular modeling based analogs will be evaluated for metastasis inhibitory effectiveness in various in vivo and in vitro biological assays. 2./ Development of HIV integrase enzyme inhibitory agents. Integrase is an HIV specific enzyme that is required for the integration of the viral genome into its targeted host (human) chromosome. Integrase does not have an obvious cellular counterpart, therefore inhibitors developed to it may not be toxic to mammalian cells. Based on our extensive structure / activity studies we have discovered a redox stable homodimeric hexapeptide that effectively inhibits integrase at 4 microM concentration. Structural considerations suggest that this agent may be the first example where one molecule of inhibitor optimally fit into the two adjacent inhibitory sites of asymmetric trimeric subunits of the enzyme. As such, this tryptophan rich homodimer should provide for a new pharmacophore model for developing novel HIV integrase enzyme inhibitors, and subsequently anti-HIV therapeutics.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Sun, Haiying; Nikolovska-Coleska, Zaneta; Chen, Jianyong et al. (2005) Structure-based design, synthesis and biochemical testing of novel and potent Smac peptido-mimetics. Bioorg Med Chem Lett 15:793-7
Koehler, Niklas K U; Yang, Chao-Yie; Varady, Judith et al. (2004) Structure-based discovery of nonpeptidic small organic compounds to block the T cell response to myelin basic protein. J Med Chem 47:4989-97
Sun, Haiying; Nikolovska-Coleska, Zaneta; Yang, Chao-Yie et al. (2004) Structure-based design of potent, conformationally constrained Smac mimetics. J Am Chem Soc 126:16686-7
Nikolovska-Coleska, Zaneta; Wang, Renxiao; Fang, Xueliang et al. (2004) Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. Anal Biochem 332:261-73
Krajewski, Krzysztof; Marchand, Christophe; Long, Ya-Qiu et al. (2004) Synthesis and HIV-1 integrase inhibitory activity of dimeric and tetrameric analogs of indolicidin. Bioorg Med Chem Lett 14:5595-8
Sun, Haiying; Nikolovska-Coleska, Zaneta; Yang, Chao-Yie et al. (2004) Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site. J Med Chem 47:4147-50
Nikolovska-Coleska, Zaneta; Xu, Liang; Hu, Zengjian et al. (2004) Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 47:2430-40
Song, Yan-Li; Roller, Peter P; Long, Ya-Qiu (2004) Development of l-3-aminotyrosine suitably protected for the synthesis of a novel nonphosphorylated hexapeptide with low-nanomolar Grb2-SH2 domain-binding affinity. Bioorg Med Chem Lett 14:3205-8
Li, Peng; Peach, Megan L; Zhang, Manchao et al. (2003) Structure-based design of thioether-bridged cyclic phosphopeptides binding to Grb2-SH2 domain. Bioorg Med Chem Lett 13:895-9
Krajewski, Krzysztof; Long, Ya-Qiu; Marchand, Christophe et al. (2003) Design and synthesis of dimeric HIV-1 integrase inhibitory peptides. Bioorg Med Chem Lett 13:3203-5

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