Biomimetic Synthesis of Cyclic Peptides Using Thioethylamido Thioester

Biomimetic Synthesis of Cyclic Peptides Using Thioethylamido Thioester

Biomimetic Synthesis of Cyclic Peptides Using Thioethylamido Thioester (#26)

James Tam ¹

School of Biological Sciences, Nanyang Technological University, Singapore

Intein-mediated protein splicing involves four acyl shift reactions to excise an intein and to ligate the flanking exteins to form a new protein. Here we report a biomimetic method exploiting these acyl shift reactions through a C-terminal peptide or linker containing a thioethylamido (TEA) moiety to mediate the breaking and making of peptide bonds suitable for preparing peptide thioesters and ligation reactions to afford peptides and circular proteins. The thioethylamido (TEA) moiety is an essential functional group present in Cys, MeCys(Trt) and simplified analogs such as thioethylalkyl amines, and which will undergo an acid-catalyzed N-S acyl shift to form a thioester. This thioester was exploited to undergo an S-S exchange exchange reaction in tandem either intermolecularly or intramolecularly to a new thioester or a thiolactone, respectively, and the C-terminal TEA-containing moiety excised similar to the intein splicing. The efficiency and side reactions of these tandem thiol switch reactions mediated by Cys, MeCys, and thioethylalkyl amines will be discussed. Our scheme is fully compatible with Fmoc synthesis.

Authors contributing to this presentation.

Tam, J

Lee Wee Nam Chair Professor, School of Biological Sciences, Director, Herbalomics and Drug Discovery, School of Biological Sciences, Nanyang Technological University, Singapore James P. Tam is the Director of the Herbalomics and Drug Discovery Laboratory. He served as the Founding Dean of the School of Biological Sciences, the Founding Director of Biological Research Center and the Founding director of the double-degree program in Biomedical Science and Chinese Medicine at Nanyang Technological University, Singapore. He received his Ph.D. in Medicinal Chemistry from the University of Wisconsin, Madison, USA and held appointments as Associate Professor at The Rockefeller University, USA (1982-1991), Professor at Vanderbilt University, USA (1991-2004) and The Scripps Research Institute, USA (2004-2008). His research work focuses on the discovery, design and development of therapeutics, particularly orally active biologics, immunologics, anti-infectives, anti-proliferatives and synthetic vaccines. Professor Tam has published more than 330 papers in these areas of research. He received the Vincent du Vigneaud Award in 1986, the Rao Makineni Award by American Peptide Society in 2003, the Ralph F. Hirschmann Award by the American Chemical Society (ACS) in 2005, the Merrifield Award by American Peptide Society in 2013 and the Akabori Memorial Award by the Japanese Peptide Society (JPS) in 2016 for the outstanding contributions to peptide and protein sciences. The Merrifield, Hirschmann and Akabori Awards, administered by the APS, ACS and JPS respectively, recognize the highest achievements in the chemistry, biochemistry and biophysics of peptides at an international level. In addition to his scientific research, he has also been active in the peptide community. Besides serving on many editorial boards, he organizes international peptide and protein symposia and was co-founder of the past ten International Chinese Peptide Symposia. He received the Cathay Award from the Chinese Peptide Society, China in 1996. He was also honored as Honorary Professor by Peking University and Peking Union Medical College.

Biomimetic Synthesis of Cyclic Peptides Using Thioethylamido Thioester (#26)

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Tam, J

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