Research
Chemical
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Bioorganic
Chemistry
Organic
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Green
Chemistry
Peptide
Synthesis
Photo-
chemistry
Photo-
chemistry
Peptides are an incredibly important class of therapeutic agents, with more than 60 peptide drugs on the market and over 350 in clinical and preclinical development. However, the iterative assembly of peptides by solid-phase peptide synthesis (SPPS) is among the most wasteful and poorly atom economical chemical processes. An estimated five metric tons of waste are generated for every kilogram of peptide produced. Therefore, there is a critical need to develop more sustainable technologies to access this important class of molecules.
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Chromatography-free Cyclic Peptide Synthesis
The enhanced proteolytic stability, rigidity, and ability to target protein-protein interactions (PPIs) make cyclic peptides attractive scaffolds for drug development. However, cyclic peptides remain notoriously difficult to prepare by conventional SPPS. Moreover, to separate truncated byproducts and linear sequences that failed to cyclize, extensive HPLC purification is required. Annually, 11 million liters of mixed organic and aqueous waste is attributed to HPLC alone. Research in this area will focus on the development of a novel chromatography-free technology to access this privileged class of molecules.
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Universal Method of Resin Recycling
SPPS is the most common approach to prepare synthetic peptides. During SPPS, the peptide is covalently attached to an insoluble polymeric support (resin). An often-overlooked waste product of SPPS is the resin itself. After a successful peptide synthesis, the peptide is released from the solid support, and the spent resin is typically disposed of in a mixed solid waste stream. In this project, we focus on developing a novel method of resin recycling that is universal, as our technology is independent of the resin-type and linker used.
Inverse SPPS
Peptides are routinely prepared by SPPS in the non-biological (C → N) direction. However, some of the most important C-terminally modified peptides are difficult to prepare due to the nature of the peptide linkage to the resin. The focus of this research is aimed to open the combinatorial chemistry toolbox and synthesize peptides in the inverse (N → C) direction. Toward this end, our goal is to develop especially atom efficient and green methods for amide bond formation.
References
(1) Isidro-Llobet, A.; Kenworthy, M. N.; Mukherjee, S.; Kopach, M. E.; Wegner, K.; Gallou, F.; Smith, A. G.; Roschangar, F. Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production. J. Org. Chem. 2019, 84 (8), 4615–4628.
(2) Merrifield, R. B. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J. Am. Chem. Soc. 1963, 85 (14), 2149–2154.
(3) Ritter, S. K. Five Green Chemistry Success Stories. Chem Eng News 2017, 95, 16.
(4) Zorzi, A.; Deyle, K.; Heinis, C. Cyclic Peptide Therapeutics: Past, Present and Future. Curr. Opin. Chem. Biol. 2017, 38, 24–29.
(5) Giaquinto,J.R.;Samide,M.J.CleaningandRecyclingMobilePhaseforChromatographicSeparations. ACS Sustain. Chem. Eng. 2013, 1 (10), 1225–1230.