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Manipulating biological macromolecules through reversible absorption to a solid support (RASS)

Abstract:

The paradigm setting concept of solid phase peptide synthesis relies on the covalent attachment of a growing macromolecule to an insoluble solid support to produce a peptide-resin polymer network. Once synthesized, purification and handling of peptides is dominated by non covalent adsorption onto a variety of supports such as those used for chromatography. The utility of this Reversible Absorption to a Solid Support (RASS) for facilitating synthetic transformations on macromolecules has been recently explored in our lab. We find that the approach has potential to improve peptide handling over multiple step bioconjugation reactions, as well as facilitating the transfer of unprotected peptides to organic solvent to facilitate selective reactions requiring a strong base. In related work, the structural diversity of DNA Encoded Libraries has been limited since the hydrophilic, unprotected nature of the DNA tag severely limits the repertoire of compatible chemical reactions. Rather than pursuing the optimization of individual synthetic organic reactions for water compatibility, we reasoned that a general strategy for transferring DNA-substrates into organic solvents could significantly expand the structural diversity explored by DEL. This RASS strategy was adapted for DEL through a polystyrene based, quaternary ammonium resin. Adsorption of DNA headpiece substrates to this resin was found to facilitate transfer to organic solvents such as DMA, THF, and CH₂Cl₂. This RASS approach for DEL has enabled the development of Ni-mediated carbon-carbon (C(sp2)-C(sp3)) and carbon-heteroatom (C-N, C-S, C-P) cross couplings with broad substrate scope and with excellent DNA compatibility. The immobilization of the DNA has also facilitated the use of electrochemical transformations. This expanded scope of reaction conditions compatible with DEL library generation has the promise to contribute to the generation of conformationally diverse scaffolds with drug-like properties. Finally, a general approach for modification of unprotected natural oligonucleotides at the 3’ and 5’ hydroxyl group will be presented.

Bio:

Philip Dawson is the dean of Graduate and Postdoctoral Studies at Scripps Research and a professor in the Department of Chemistry. As dean, he oversees the Skaggs Graduate School of Chemical and Biological Sciences, a program consistently ranked among the top 10 in the nation.

Dawson’s research focuses on the development of synthetic tools for the chemical synthesis of proteins and bioconjugation. For his accomplishments in this field, he has received the Alfred P. Sloan Foundation Fellowship, the Vincent du Vigneaud Award from the American Peptide Society, the Max Bergmann Gold Medal for outstanding contributions in peptide chemistry and the Leonidas Zervas Award from the European Peptide Society.

He has served on the advisory boards of numerous journals, companies and international conferences. Additional contributions have been made as a member of the board of directors for the Federation of American Societies for Experimental Biology and as the president of the American Peptide Society. His studies have been reported in more than 150 peer-reviewed publications.

Dawson earned his doctorate at the Institute’s graduate program in 1996, following his bachelor’s degree in chemistry from Washington University in St. Louis. He pursued postdoctoral work at the California Institute of Technology before returning to Scripps Research as an assistant professor. In 2011, he served on the Dean’s Advisory Committee and in 2012, became associate dean of Graduate Studies. In 2017, Dawson became a full professor and was appointed to his current position.

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