eBriefing

From Peptides to Polymers: Molecular Probes for Biological Investigation

From Peptides to Polymers
Reported by
Megan Stephan

Posted August 18, 2008

Overview

Chemical biologists seek to design new chemical tools for use in research and medicine. Their search is predicated on the incredible diversity of chemical structures, both natural and otherwise. This diversity was well represented at the Chemical Biology Discussion Group's Special Year-End Meeting, held June 2, 2008.

Molecules represented ranged from nucleic acids to peptides to small drug-like compounds. Keynote speaker Michael Famulok of the Universität Bonn described his work using aptamers, small, highly structured nucleic acids, to screen small molecule libraries for potential drug compounds. Famulok has used aptamers to identify new inhibitors of human immunodeficiency virus (HIV) replication, as well as inhibitors of a class of proteins involved in cytoskeletal remodeling known as cytohesins. His work on cytohesins has identified interesting new roles for these proteins in insulin receptor signaling and metabolic regulation. Famulok was followed by six graduate students who presented their work on a wide range of topics.

Web Sites

DNA Nanotechnology
Information on engineered DNA structures and their uses in nanotechnology from Ned Seeman's laboratory at New York University.

DNA–RNA–Protein: Translation
A refresher course on the process of protein translation.

The Ellington Lab Aptamer Database
Comprehensive, annotated repository for information about aptamers and in vitro selection.

Fertilization: Sperm/Egg Recognition and Contact
Concise summary of recognition events during the process of mammalian fertilization.

Norine Database of Nonribosomal Peptides
Database containing information on more than 700 nonribosomal peptides found in bacteria and fungi.

The Quorum Sensing Site
Compendium of quorum sensing research prepared by the University of Nottingham Quorum Sensing Research Group.

The Tp53 Web Site: p53 Information
Reference site on the role of p53 in cancer including information on its interactions with MDM2, a homolog to HDM2.


Journal Articles

Michael Famulok

Hafner M, Schmitz A., Grüne I., et al. 2006. Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature 444: 941-944.

Hafner M, Vianini E, Albertoni B, et al. 2008. Displacement of protein-bound aptamers with small molecules screened by fluorescence polarization. Nature Protoc. 3: 579-587.

Najafi-Shoushtari SH & Famulok M. 2007. Modular reporter hairpin ribozymes for analyzing molecular interactions. Methods Mol. Biol. 38: 19-24.

Yu Liu

Liu Y, Kuzuya A, Sha R, et al. 2008. Coupling across a DNA helical turn yields a hybrid DNA/organic catenane doubly tailed with functional termini. J. Am. Chem. Soc. 130: 10882-10883.

Liu Y, Sha R, Wang R, et al. 2008. 2',2'-Ligation demonstrates the thermal dependence of DNA-directed positional control. Tetrahedron 64: 8417-8422.

Liu Y, Wang R, Ding L, Sha R, et al. 2008. Thermodynamic analysis of nylon nucleic acids. Chembiochem. 2: 1641-1648.

Seeman NC. 2007. An overview of structural DNA nanotechnology. Mol. Biotechnol. 37: 246-257.

Zhu L, Lukeman PS, Canary JW, Seeman NC. 2003. Nylon/DNA: single-stranded DNA with a covalently stitched nylon lining. J. Am. Chem. Soc. 125: 10178-10179. (PDF 72.5 KB) Full Text

Philip Effraim

Forster A, Tan Z, Nalam MNL, et al. 2003. Programming peptidomimetic syntheses by translating genetic codes designed de novo. Proc. Natl. Acad. Sci. USA 100: 6353-6357. Full Text

Koh JT, Cornish VW, PG Schultz. 1997. An experimental approach to evaluating the role of backbone interactions in proteins using unnatural amino acid mutagenesis. Biochemistry 36: 11314-11322.

Mendel D, Cornish VW, PG Schultz. 1995. Site-directed mutagenesis with an expanded genetic code. Ann. Rev. Biophys. Biomol. Struct. 24: 435-462.

Tan Z, Blacklow SC, Cornish VW, Forster AC. 2005. De novo genetic codes and pure translation display. Methods 36: 279-290.

Tan Z, Forster AC, Blacklow SC, VW Cornish. 2004. Amino acid backbone specificity of the Escherichia coli translation machinery. J. Am. Chem. Soc. 126: 12752-12753.

Zhang B, Tan Z, Dickson LG, et al. 2007. Specificity of translation for N-alkyl amino acids. J. Am. Chem. Soc. 129: 11316-11317.

Elizabeth George Cisar

Geisinger E, George EA, Muir TW, Novick RP. 2008. Identification of ligand specificity determinants in AgrC, the Staphylococcus aureus quorum-sensing receptor. J. Biol. Chem. 283: 8930-8938.

George EA, Muir TW. 2007. Molecular mechanisms of agr quorum sensing in virulent staphylococci. Chembiochem. 8: 847-855.

George EA, Novick RP, Muir TW. 2008. Cyclic peptide inhibitors of staphylococcal virulence prepared by Fmoc-based thiolactone peptide synthesis. J. Am. Chem. Soc. 130: 4914-4924.

George EA, Wright JS III, Novick RP, Muir TW. 2005. Synthesis of dimeric quorum sensing peptides to probe virulence in S. aureus. Biopolymers 80: 541.

Lyon GJ, Wright JS, Muir TW & Novick RP. 2002. Key determinants of receptor activation in the agr autoinducing peptides of Staphylococcus aureus. Biochemistry 41: 10095-10104.

Muir TW. 2003. Turning virulence on and off in Staphylococci. J. Pept. Sci. 9: 612-619.

Wright JS III , Lyon GJ, George EA, et al. 2004. Hydrophobic interactions drive ligand-receptor recognition for activation and inhibition of staphylococcal quorum sensing. Proc. Natl. Acad. Sci. USA 101: 16168-16173. Full Text

Justin Cisar

Cisar JS, Tan DS. 2008. Small molecule inhibition of microbial natural product biosynthesis — An emerging antibiotic strategy. Chem. Soc. Rev. 37: 1320-1329.

Cisar JS, Ferreras JA, Soni RK, et al. 2007. Exploiting ligand conformation in selective inhibition of non-ribosomal peptide synthetase amino acid adenylation with designed macrocyclic small molecules. J. Am. Chem. Soc. 129: 7752–7753.

Ferreras JA, Ryu, J-S, Di Lello F, et al. 2005. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nature Chem. Biol. 1: 29–32.

Ferreras JA, Stirrett KL, Lu X, et al. 2008. Mycobacterial phenolic glycolipid virulence factor biosynthesis: Mechanism and small-molecule inhibition of polyketide chain initiation. Chem. Biol. 15: 51–61.

Song J, Cisar JS, Bertozzi CR. 2004. Functional self-assembling bolaamphiphilic polydiacetylenes as colorimetric sensor scaffolds. J. Am. Chem. Soc. 126: 8459–8465.

Elizabeth Harker

Guarracino DA, Chiang HR, Banks TN, et al. 2006. Relationship between salt-bridge identity and 14-helix stability of ß3-peptides in aqueous buffer. Org. Lett. 8: 807-810.

Kritzer JA, Hodsdon ME, Schepartz A. 2005. Solution structure of a β-peptide ligand for hDM2. J. Am. Chem. Soc. 127: 4118-4119.

Kritzer JA, Stephens OM, Guarracino DA, et al. 2005. β-peptides as inhibitors of protein–protein interactions. Bio. Med. Chem. 13: 11-16.

Kritzer JA, Tirado-Rives J, Hart SA, et al. 2005. Relationship between side chain structure and 14-helix stability of β3-peptides in water. J. Am. Chem. Soc. 127: 167-178.

Kritzer JA, Zutshi R, Cheah M, et al. 2006. Miniature protein inhibitors of the p53-hDM2 interaction. ChemBioChem 7: 29-31.

Keith Baessler

Baessler K, Lee Y, Roberts KS, et al. 2006. Multivalent fertilin β oligopeptides: the dependence of fertilization inhibition on length and density. Chem. Biol. 13: 251-259. Full Text

Konkar S, Gupta S, NS Sampson. 2004. Fertilin β liposomes inhibit in vitro fertilization by steric stabilization. Bioorg. Med. Chem. Lett. 4: 1381-1384.

Roberts, SK, Konkar S, NS Sampson. 2003. Comparison of fertilin β peptide-substituted polymers and liposomes as inhibitors of in vitro fertilization. ChemBioChem 4: 1229-1231.

Speakers

Michael Famulok, PhD

e-mail | web site | publications

Michael Famulok is a professor of biochemistry and bioorganic chemistry at Rheinische Friedrich-Wilhelms-Universität Bonn, Germany. He received his PhD from the University of Marburg, Germany and was a postdoctoral fellow at Massachusetts Institute of Technology and Massachusetts General Hospital/Harvard University.

Philip Effraim

e-mail | web site

Philip Effraim is an MD/PhD student completing graduate work in the laboratory of Virginia Cornish at Columbia University.

Elizabeth George Cisar

e-mail | web site | publications

Beth George is a Training Program in Chemical Biology (TPCB) graduate fellow in the laboratory of Tom Muir at the Rockefeller University.

Justin Cisar

e-mail | web site | publications

Justin Cisar is a Training Program in Chemical Biology (TPCB) graduate student in the laboratory of Derek Tan at Memorial Sloan Kettering Cancer Center.

Elizabeth Harker

e-mail | web site | publications

Elizabeth Harker is a graduate student in the laboratory of Alanna Schepartz at Yale University.

Keith Baessler

e-mail | web site | publications

Keith Baessler is a graduate student in the laboratory of Nicole Sampson at SUNY, Stony Brook.

Yu Liu

e-mail | web site | publications

Yu Liu is a graduate student in the laboratory of James Canary at New York University.


Megan Stephan
Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.