This is a long-term research program to develop mild chemical methods for peptide synthesis. These studies are based on the idea of orthogonal protection, particularly by use of the N alpha- dithiasuccinoyl (Dts) amino protecting group and the related class of open-chain carbamoyl disulfides of primary and secondary amines that were developed under this grant. These protecting groups can be rapidly and quantitatively removed under essentially neutral conditions by reduction with thiols and other agents. They are applied for solid-phase peptide synthesis in conjunction with anchoring linkages that are cleavable by mild acid, light, or fluoride ion. A major goal of this grant so far has been the preparation and application of a complete set of orthogonally protected N alpha- Dts amino acid derivatives to the solid-phase synthesis of biologically active peptides. A general method has been developed to cleanly introduce the Dts group onto amino acids, and of the twenty genetically encoded residues, only histidine remains to be appropriately derivatized. Even so, there is a need for further improvements in the preparative conditions with an eye to scale-up for commercial production; promising experiments to achieve this are already underway. Furthermore, studies are planned to settle remaining questions of how to deal with complex residues as asparagine, glutamine, arginine, histidine, cysteine, and tryptophan. Recently published work from this laboratory details protocols for the synthesis of peptides up to a length of ten residues. In every case where Dts-based and other methodologies have been examined side-by-side in a controlled fashion, results with Dts have been demonstrably superior. It remains for the present granting period to demonstrate that substantially longer peptides can be made in significantly better yields and purities than by previous methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM028934-07A1
Application #
3276321
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1981-04-01
Project End
1990-12-31
Budget Start
1988-01-20
Budget End
1988-12-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Arts and Sciences
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Barany, George; Britton, Doyle; Chen, Lin et al. (2015) Unexpectedly Stable (Chlorocarbonyl)(N-ethoxycarbonylcarbamoyl)disulfane, and Related Compounds That Model the Zumach-Weiss-Kühle (ZWK) Reaction for Synthesis of 1,2,4-Dithiazolidine-3,5-diones. J Org Chem 80:11313-21
Barany, Michael J; Hammer, Robert P; Merrifield, R B et al. (2005) Efficient synthesis of 1,2,4-dithiazolidine-3,5-diones [dithiasuccinoyl-amines] from bis(chlorocarbonyl)disulfane plus bis(trimethylsilyl)amines. J Am Chem Soc 127:508-9
Xu, Q; Barany, G; Hammer, R P et al. (1996) Efficient introduction of phosphorothioates into RNA oligonucleotides by 3-ethoxy-1,2,4-dithiazoline-5-one (EDITH). Nucleic Acids Res 24:3643-4
Xu, Q; Musier-Forsyth, K; Hammer, R P et al. (1996) Use of 1,2,4-dithiazolidine-3,5-dione (DtsNH) and 3-ethoxy-1,2,4-dithiazoline-5-one (EDITH) for synthesis of phosphorothioate-containing oligodeoxyribonucleotides. Nucleic Acids Res 24:1602-7
Ottinger, E A; Hui, T Y; Man, Z et al. (1995) In vitro association of the phosphatidylinositol 3-kinase regulatory subunit (p85) with the human insulin receptor. Int J Pept Protein Res 46:346-53
van Abel, R J; Tang, Y Q; Rao, V S et al. (1995) Synthesis and characterization of indolicidin, a tryptophan-rich antimicrobial peptide from bovine neutrophils. Int J Pept Protein Res 45:401-9
Andreu, D; Albericio, F; Sole, N A et al. (1994) Formation of disulfide bonds in synthetic peptides and proteins. Methods Mol Biol 35:91-169
Ottinger, E A; Shekels, L L; Bernlohr, D A et al. (1993) Synthesis of phosphotyrosine-containing peptides and their use as substrates for protein tyrosine phosphatases. Biochemistry 32:4354-61
Albericio, F; Barany, G (1993) Acidolytic cleavage of tris(alkoxy)benzylamide (PAL) ""internal reference"" amino acyl (IRAA) anchoring linkages: validation of accepted procedures in solid-phase peptide synthesis (SPPS). Int J Pept Protein Res 41:307-12
Munson, M C; Lebl, M; Slaninova, J et al. (1993) Solid-phase synthesis and biological activity of the parallel dimer of deamino-oxytocin. Pept Res 6:155-9

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