It has been estimated that 80% of the protein products of the human genome are "undruggable" because they either lack deep hydrophobic pockets that can bind small molecules or they are inside cells where antibodies and other biological drugs cannot reach them. A goal of my group is to develop molecules that can bind these undruggable proteins and penetrate cells to create new therapeutics and molecular tools to probe biology. We have developed a unique approach to the synthesis of chemically functionalized macromolecules with programmable shapes. We have developed the synthesis of a collection of chiral, cyclic building blocks that we connect through pairs of amide bonds to create complex and pre-organized spiro-ladder oligomers, called bis- peptides, between 500 and 2,000 Daltons in weight. We have recently discovered new chemistry that allows us to incorporate a functional group on every building block. We have developed this chemistry to the point where we can create highly functionalized macromolecules that can present proteogenic and non-proteogenic groups in any three- dimensional arrangement required. In terms of "diversity oriented synthesis" these oligomers have very diverse three-dimensional structures by virtue of their constrained nature and rich stereochemistry. We propose to use this synthetic methodology to create functionalized bis-peptides that will mimic short ?-helices to bind helix binding proteins;mimic long ?-helices to disrupt coiled-coils;and identify protein-protein interactions in the Brookhaven Protein Data Bank that can be targeted using these oligomers. In preliminary results we have demonstrated a functionalized bis-peptide that binds Mdm2 with higher affinity than the wild-type p53 peptide and is taken up by cells. We propose to develop functionalized bis-peptides that simultaneously bind Mdm2 and Mdmx and others that bind c-Myc and study their ability to enter and arrest growth in liver cancer cells.
"Undruggable proteins" are the estimated 80% of human proteins that are inside cells and thus unreachable by protein therapeutics and that cannot bind small molecule drugs because they lack a deep hydrophobic pocket. We are developing a general approach to synthesizing shape-programmable molecules between 500 - 2,000 Daltons that are able to display diverse functionality to bind protein surfaces as proteins do while still penetrating cells as small molecules do. These molecules will bridge the gap between small molecule and protein therapeutics and allow us to target disease related proteins that are currently considered undruggable.
|Zhao, Qingquan; Schafmeister, Christian E (2015) Synthesis of Spiroligomer-Containing Macrocycles. J Org Chem 80:8968-78|
|Parker, Matthew F L; Osuna, SÃlvia; Bollot, Guillaume et al. (2014) Acceleration of an aromatic Claisen rearrangement via a designed spiroligozyme catalyst that mimics the ketosteroid isomerase catalytic dyad. J Am Chem Soc 136:3817-27|
|Kheirabadi, Mahboubeh; Ã‡elebi-Ã–lÃ§Ã¼m, Nihan; Parker, Matthew F L et al. (2012) Spiroligozymes for transesterifications: design and relationship of structure to activity. J Am Chem Soc 134:18345-53|
|Brown, Zachary Z; Akula, Kavitha; Arzumanyan, Alla et al. (2012) A spiroligomer *-helix mimic that binds HDM2, penetrates human cells and stabilizes HDM2 in cell culture. PLoS One 7:e45948|
|Brown, Zachary Z; Schafmeister, Christian E (2010) Synthesis of hexa- and pentasubstituted diketopiperazines from sterically hindered amino acids. Org Lett 12:1436-9|
|Gupta, Sharad; Schafmeister, Christian E (2009) Synthesis of a carboxylate functionalized bis-amino acid monomer. J Org Chem 74:3652-8|
|Chakrabarti, Subhasis; Parker, Matthew F L; Morgan, Christopher W et al. (2009) Experimental evidence for water mediated electron transfer through bis-amino acid donor-bridge-acceptor oligomers. J Am Chem Soc 131:2044-5|
|Bird, Gregory H; Pornsuwan, Soraya; Saxena, Sunil et al. (2008) Distance distributions of end-labeled curved bispeptide oligomers by electron spin resonance. ACS Nano 2:1857-64|
|Schafmeister, Christian E; Brown, Zachary Z; Gupta, Sharad (2008) Shape-programmable macromolecules. Acc Chem Res 41:1387-98|
|Brown, Zachary Z; Schafmeister, Christian E (2008) Exploiting an inherent neighboring group effect of alpha-amino acids to synthesize extremely hindered dipeptides. J Am Chem Soc 130:14382-3|
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