Matthew C.T. Hartman
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Assistant professor |
Education
B.S. Wheaton College
Ph.D. University of Michigan
Research interests
Non-ribosomal peptides are highly modified peptides produced by a wide variety of fungi and microorganisms. Many of these molecules such as cyclosporin A, vancomycin and daptomycin are endowed with amazing biological activity; for this reason it would be of great interest to prepare diverse libraries of peptides like these.
Unfortunately, the complexity of the biosynthetic machinery used to make these molecules has prevented their manipulation for the production of large numbers of variants. An alternative approach for making peptide libraries, solid-phase peptide synthesis, also has its limitations; typically library size is limited to 10^7 unique peptides. Moreover, cyclization of the solid phase prepared peptides to make them more like NRPs continues to be a challenge.
On the other hand, biosynthetic techniques like mRNA display or ribosome display allow the routine preparation of peptide libraries on the order of 10^13 molecules, fully 6 orders of magnitude greater than other techniques. Unfortunately, these libraries are typically limited by the non-bioavailable proteinogenic 20 AA building blocks.
To circumvent this problem, we have found over 55 unnatural building blocks that are compatible with mRNA display. Moreover, we can cyclize libraries of peptides containing these building blocks efficiently using a method based on cysteine bis-alkylation.
Despite these initial successes, the cyclic peptides produced by this method still do not completely resemble the highly-backbone modified NRPs. Two key barriers still exist; the lack of diversity of the building blocks, and the problem of cell permeability.
The method development projects in the lab are aimed at solving these two problems:
1. Development of a simple method for attaching any amino acid to any tRNA.
Current approaches for charging tRNAs are limited by either their scope or difficulty. We are working on methods to overcome these limitations using chemoselective tRNA ligations.
2. Discovery of cell-permeable peptides. We are using screens to find peptide building blocks that promote cell permeability and selections to find peptides within those libraries that are cell permeable.
Using these improved libraries we will select for cell-permeable ligands and inhibitors for use as drugs and tools in cancer biology.
Selected References:
- M.C.T. Hartman, K. Josephson, and J.W. Szostak, Enzymatic aminoacylation of tRNA with unnatural amino acids. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 4356-4361.
- K. Josephson, M.C.T. Hartman, and J.W. Szostak, Ribosomal Synthesis of Unnatural Peptides. J. Am. Chem. Soc. 2005, 127, 11727-11735.
