个人简介

Anna Mapp completed her A.B. in chemistry at Bryn Mawr College before moving to the University of California-Berkeley to complete the PhD under the direction of Professor Clayton H. Heathcock. Following postdoctoral work with Professor Peter B Dervan at Caltech, Mapp joined the faculty at the University of Michigan in 2000, where she is currently Professor of Chemistry and Director of the Program in Chemical Biology.

研究领域

Bioorganic Chemistry Chemical Biology Nano Chemistry Organic Chemistry New Synthetic Methods

Organic synthesis offers powerful tools for addressing questions of biological importance, but the answers to such questions are often limited by the scope of available synthetic methods. Thus, as we seek to unravel complex biological processes, we simultaneously focus on the development of new synthetic approaches with a variety of applications. Much of our research focuses upon developing a molecular-level picture of inducible gene expression in eukaryotes using organic molecules as mechanistic probes. Regulated gene expression is critical for cellular existence, and a number of human diseases such as cancer and diabetes have been linked to aberrant patterns of gene expression. Therefore, a goal of primary importance in the scientific community is the discovery of transcription-based therapeutics capable of reprogramming gene expression in diseased cells while leaving normal cells unaffected. While a general sequence of events that leads to gene up-regulation is agreed upon, the molecular-level interactions that regulate the levels and time course of transcriptional activation remain unknown. A more detailed picture of gene regulation is a prerequisite for the eventual development of transcription-based therapeutics. We have developed two approaches for identifying the relevant targets of activator proteins in the transcriptional machinery, understanding how multiple activator proteins function synergistically to up-regulate transcription, and uncovering the regulatory role of transcriptional machinery composition. We use an ELISA screen to identify ligands for individual protein components of the transcriptional machinery from combinatorial libraries. The selected ligands are characterized through fluorescence and cross-linking experiments and can then be used in functional competition assays both in vitro and in vivo. These data coupled with BLAST searches of the yeast genome are used to identify interactions governing the organization of the eukaryotic transcriptional machinery. A second approach is the design and synthesis of organic molecules that mimic common protein structural motifs such as the helix. The structure of each designed scaffold is governed by the stereochemical relationships within the molecule, and the synthesis of the scaffold thus requires a stereocontrolled approach. Our synthetic approach has applications beyond the designed scaffolds, including a potentially general strategy for the selective synthesis of b-amino acids, a class of structures present in a variety of natural products and other biologically active molecules.

近期论文

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Majmudar, C.Y.; Hojfeldt, J.W.; Arevang C.J.; Pomerantz, W.C.; Gagnon, J.K.; Schultz P.J.; Cesa, L.C.; Doss, C.H.; Rowe, S.P.; Vasquez, V.; Tamayo-Castillo, G.; Cierpicki, T.; Brooks, C.L. 3rd; Sherman, D.H.; Mapp, A.K. "Sekikaic Acid and Lobaric Acid Target a Dynamic Interface of the Coactivator CBP/p300." Angew. Chem. Int. Ed. 2012, (Epub ahead of print). [PDF] [HTML] Thompson, A.D.; Dugan, A.; Gestwicki, J.E.; Mapp, A.K. "Fine-tuning multi-protein complexes using small molecules." ACS Chem Biol. 2012, (Epub ahead of print) [PDF] Pomerantz, W.C.; Wang, N; Lipinski, A.K.; Wang, R; Cierpicki, T.; Mapp, A.K. "Profiling the dynamic interfaces of fluorinated transcription complexes for ligand discovery and characterization." ACS Chem Biol. 2012, (Epub ahead of print) [PDF] Taylor, C.E.; Pan, Q; Mapp A.K. "Synergistic enhancement of the potency and selectivity of small molecule transcriptional inhibitors." ACS Med Chem Lett. 2012, 3(1):30-34. [PDF][HTML] Krishnamurthy, M.; Dugan, A.; Nwokoye, A.; Fung, Y., Lancia, J.; Majmudar, C.Y.; Mapp, A.K. "Caught in the act: covalent cross-linking captures activator-coactivator interactions in vivo." ACS Chem Biol. 2011, 6(12):1321-6. [PDF][HTML] Hojfeldt, J.W.; Van Dyke, A.R.; Mapp, A.K. "Transforming ligands into transcriptional regulators: building blocks for bifunctional molecules." Chem. Soc. Rev. 2011, 40(8),4286-4294. [PDF][HTML] Wands, A.M.; Wang, N.; Lum, J.K.; Hsieh, J.; Fierke, C.A.; Mapp, A.K. "Transient-state kinetic analysis of transcriptional activator-DNA complexes interacting with a key coactivator." J. Biol. Chem. 2011, 286(18):16238-16245.[PDF][HTML] Bates, C.A.; Pomerantz, W.C.; Mapp, A.K. "Transcription tools: Small molecules for modulating CBP KIX-dependent transcriptional activators." Biopolymers, 2011, 95(1),17-23.[PDF][HTML] Danowitz, A.M.; Taylor, C.E.; Shrikian, T.M.; Mapp, A.K. "Palladium-catalyzed [3,3]-rearrangement for the facile synthesis of allenamides." Org. Lett.2010, 12(11), 2574-7.[PDF][HTML] Lee, L.W.; Mapp, A.K. " Transcriptional switches: chemical approaches to gene regulation." J. Biol. Chem. 2010, 285(15), 11033-8. [PDF][HTML] Lee, L.W.; Taylor, C.E.; Desaulniers, J.P.; Zhang, M.; Hojfeldt, J.W.; Pan, Q.; Mapp, A.K. "Inhibition of ErbB2(Her2) expression with small molecule transcription factor mimics." Bioorg Med Chem Lett 2009, 19(21), 6233-6.[PDF][HTML][Supporting Info] Majmudar, C.Y.; Lee, L.W.; Lancia, J.K.; Nwokoye, A.; Wang, Q.; Wands, A.M.; Wang, L.; Mapp, A.K. "Impact of Nonnatural Amino Acid Mutagenesis on the in Vivo Function and Binding Modes of a Transcriptional Activator." J. Am. Chem. Soc. 2009, 131(40), 14240-2. [Abstract][PDF][HTML][Supporting Info] Majmudar, C.Y.; Wang, B.; Lum, J.K.; Hakansson, K.; Mapp, A.K. "A High-Resolution Interaction Map of Three Transcriptional Activation Domains with a Key Coactivator from Photo-Cross-Linking and Multiplexed Mass Spectrometry." Angew. Chem. Intl. Ed. Engl. 2009, 48 (38), 7021-7024. [Abstract][PDF][HTML][Supporting Info] Bao, L.; Gorin, M.A.; Zhang, M.; Ventura, A.C.; Pomerantz, W.C.; Merajver, S.D.; Teknos, T.N.; Mapp, A.K.; Pan, Q. "Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer." Cancer Res. 2009, 69(14), 5829-34. [Abstract][PDF][HTML] Majmudar, C.Y.; Labut, A.E.; Mapp, A.K. "Tra1 as a screening target for transcriptional activation domain discovery." Bioorg. Med, Chem. Lett. 2009, 19(14), 3733-5. [Abstract][PDF][HTML] Aminoff, D.; Bochar, D.A.; Fuller, A.A.; Mapp, A.K.; Showalter, H.D.; Kirchhoff, P.D. "Research into slective biomarkers of erythrocyte exposure to organophosphorus compounds." Anal Biochem. 2009, 392(2), 155-61. [PDF][HTML] Buhrlage, S.J.; Bates, C.A.; Rowe, S.P.; Minter, A.R.; Brennan, B.B.; Majmudar, C.Y.; Wemmer, D.E.; Al-Hashimi, H. M.; Mapp, A.K. "Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors." ACS Chem Biol, 2009, 4(5), 335-344. [Abstract][PDF] Buhrlage, S.J.; Chen, B.; Mapp, A.K. "A flexible synthetic route to isoxazolidine b-proline analogs." Tetraherdon, 2009, 65 (16), 3305-3313. [PDF] Casey, R. J.; Desaulniers, J.-P.; Hojfeldt, J. W.; Mapp, A.K. "Expanding the repertoire of small molecule transcriptional activation domains." Bioorg. Med. Chem. 2009, 17 (3), 1034-1043. [PDF][HTML] Rowe, S.P.; Mapp, A.K. "Assessing the permissiveness of transcriptional activator binding sites." Biopolymers, 2008, 89 (7), 578-581. [PDF]