Spring, every year
Instructor: E. James Petersson (email@example.com)
Office hours by appointment.
Course Outline: This course will focus on current topics in Chemical Biology, particularly experiments in which 1) chemical synthesis enables one to probe or control biological systems in novel ways or 2) manipulation of biological systems facilitates novel chemical syntheses. As the goal of the course is to familiarize students with innovative recent experimental approaches and
to stimulate them to conceive of their own new methodology, students will be responsible for delivering presentations on topics selected from the literature and generating several novel research proposal ideas, one of which will be elaborated into a full proposal. The prepared seminar will allow students to explore topics not covered in Prof. Petersson’s lectures or to research one of those topics in more depth. The proposal will be evaluated for creativity, feasibility, and impact.
Reading: The course will draw from the primary literature. The following texts may be useful for review of 1) physical organic chemistry principles, 2) understanding organic reaction mechanisms, 3) biochemical reaction mechanisms, 4) biological pathways, 5) basic biophysics.
Seminar Dates: Oct. 27: Topic selection and scheduling of student seminars.
Students must submit an outline of their student seminar two weeks before their scheduled seminar date and meet to discuss a draft of the seminar one week in advance.
Oct. 1: First one page preproposal due.
Oct. 15: Second preproposal due.
Nov. 3: Third preproposal due.
Nov. 19: Final preproposal due.
Nov. 23–25: Student meetings to select full proposal topic.
Dec. 10: Full six-page proposal due.
Extra class sessions will be scheduled during reading period for oral presentations of the final proposals.
Exams: Three take-home exams will be given during the term, due one week after distribution. (Oct. 15, Nov. 19., Dec. 12).
Class 1: Overview
Outline of topics to be covered in the course and those available as in-class seminar topics. Discussion of chemical and biological background of course.
Class 2: Sequence-specific DNA Recognition by "Small" Molecules
From non-specific intercalators (ethidium bromide) and DNA damage agents (enediynes) to sequence-specific polymers like polyamides and peptide nucleic acids (PNAs).
Dervan, Biorg. Med. Chem. 9:2215-2235 (2001)
Hannon, Chem. Soc. Rev. 36:280-295 (2007)
Class 3: Unnatural DNA
The synthesis and enzymatic incorporation of unnatural nucleic acids into DNA backbones as stucture probes (e.g. sequencing) or for engineering purposes.
Piccirilli, Nature 343:33-37 (1990)
Kool, Angew. Chem. Int. Ed. 39:990-1009 (2000)
Hirao, Curr. Opin. Chem. Biol. 10:622-627 (2006)
Echenmoser, Science 284:2218-2124 (1999)
Class 4: RNA Aptamers, Ribozymes, and Selection
Non-coding RNAs, some discussion of the mechanism of natural RNA enzymes; focus on selection of sequences for function.
Doudna, Nature 418:222-228 (2002)
Mayer, Angew. Chem. Int. Ed. 48:2672-2689 (2009)
Class 5: Modified RNAi and Riboswitches
The basic mechanism of RNA interference (RNAi), delivery of interfering RNA to cells. Naturally occurring riboswitches as drug targets, and ways in which they can be introduced for gene control.
Gallivan, Curr. Opin. Chem. Biol. 11:612-619 (2007)
Blount, Nat. Biotechnol. 24:1558-1564 (2006)
Whitehead, Nat. Rev. Drug Disc. 8:129-138 (2009)
Class 6: Unnatural Amino Acid Mutagenesis Methodology
Review of ribosomal function. Sense codon reassignment and nonsense suppression. Compare and contrast three methods for ribosomal unnatural amino acid incorporation: chemical synthesis, ribozyme aminoacylation, 21st synthetase
Noren, Science 244:182-188 (2005)
Murikami, Nat. Meth. 3:357-359 (2006)
Wang, Angew. Chem. Int. Ed. 44:34-66 (2005)
Class 7: Unnatural Amino Acid Applications
Use of unnatural amino acids in biological experiment both in vitro and in vivo, combination with ribosomal manipulation for expanded amino acid coding
Wang, Chem. Biol. 16:323-336 (2009)
Mendel, Ann. Rev. Biophys. Biomol. Struct. 24:435-462 (1995)
Class 8: DNA- and mRNA-Templated Chemical Synthesis
Nucleic acid polymers are used to direct complex organic syntheses in both water and organic solvent. PCR amplification is also used to analyze reactions.
Takahashi, Trends Biochem. Sci. 28:159-165 (2003)
Wrenn, Ann. Rev. Biochem. 76:31-349 (2007)
Class 9: Chemical Protein Synthesis
Brief discussion of solid-phase synthesis methodology, focus on segment ligation chemistry and semi-synthetic approaches
Kent, Chem. Soc. Rev. 38:338-351 (2009)
Flavell, Acc. Chem. Res. 42:107-116 (2009)
Hackenberger, Angew. Chem. Int. Ed. 47:10030-10074 (2008)
Class 10: Manipulation of Protein Folding and Protein-Protein Interations
Fundamentals of protein-protein interactions (both inter- and intramolecular), strategies for synthetic control of secondary, tertiary, and quaternary structure.
Nilsson, Chem. Rev. 101:3153-3163 (2001)
Garner, Org. Biomol. Chem. 5:3577-3585 (2007)
Class 11: Foldamers
Non-biological polymers that adopt specific folded shapes in solution like
biomolecules. x-peptides, peptoids, modified nucleic acids, polyarylalkynes.
Gellman, Acc. Chem. Res. 31:173-180 (1998)
Goodman, Nat. Chem. Biol. 29:252-262 (2007)
Class 12: Biomolecule Labelling Technologies
Site-specific protein, polysaccharide, and nucleic acid modification with synthetic molecules, focus on chemoenzymatic routes and "bioorthogonal" reactions.
Carrico, Chem. Soc. Rev. 37:1423-1431 (2008)
Lavis, ACS Chem. Biol. 3:142-155 (2008)
Foley, Curr. Opin. Chem. Biol. 11:12-19 (2007)
Sameiro, Chem. Rev. 109:190-212 (2009)
Class 13: Engineering Small Molecule Biosynthesis
Redirection of biosynthetic pathways through directed evolution, application of unnatural substrates, or genetic engineering of multi-enzyme complexes.
Walsh, Acc. Chem. Res. 41:4-10 (2008)
Keasling, ACS Chem. Biol. 3:64-76 (2008)
Class 14: Monitoring Biomolecule Interactions
Small molecules and proteins engineered to detect transient interactions and output a signal (typically fluorescent or chemiluminescent).
Villalobos, Ann. Rev. Biomed. Eng. 9:321-349 (2007)
Giepmans, Science 312:217-224 (2006)
Class 15: Monitoring Small Molecule Chemical Messengers
Proteins, nucleic acids, or small molecules designed to report on the concentrations of small (< 1 kD) molecule concentrations in living cells.
Miller, Curr. Opin. Chem. Biol. 11:620-625 (2007)
Que, Chem. Rev. 105:1517-1549 (2008)
Class 16: "Bump and Hole" Chemical Genetics
Small molecule synthesis used in conjunction with genetic manipulation to understand signaling pathways and identify targets for pharmaceuticals.
Alaimo, Curr. Opin. Chem. Biol. 5:360-367 (2001)
Buskirk, Chem. Biol. 12:151-161 (2005)
Class 17: Photochemical Control of Cell Signaling
Techniques for incorporating photochemical triggers, either through chemical synthesis or the genetic manipulation of photo-responsive proteins.
Lee, ACS Chem. Biol. 4:409-427 (2009)
Gorostiza, Science 322:395-399 (2008)
Class 18: Geometric Control with Surfaces and Microfuidics
Precise control of surface geometry and solution flow for studying cellular interactions in defined environments; focus on applications not fabrication.
Mrksich, Chem. Soc. Rev. 29:267-273 (2000)
Kastrup, Acc. Chem. Res. 41:549-558 (2008)
Class 19: Proteomics and Metabolomics
Mass spectrometry and array-based technologies used to document changes in protein expression and activity in response to extracellular stimuli.
Cravatt, Ann. Rev. Biochem. 77:990-1009 (2000)
Cravatt, Nature 450:991-1000 (2007)
Class 20: Student Seminars
Class 21: Student Seminars
Class 22: Student Seminars
Class 23: Student Seminars
Class 24: Student Seminars
Class 25: Student Seminars
Class 26: Student Seminars