Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.

Aboye, Teshome LetaUppsala universitet,Institutionen för läkemedelskemi,Avdelningen för farmakognosi (author)

Interlocking disulfides in circular proteins : toward efficient oxidative folding of cyclotides.

Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

Clark, Richard J.Uppsala universitet,Institutionen för läkemedelskemi,Avdelningen för farmakognosi (author)
Burman, RobertUppsala universitet,Institutionen för läkemedelskemi,Avdelningen för farmakognosi(Swepub:uu)burob623 (author)
Roig, Marta BajonaUppsala universitet,Institutionen för läkemedelskemi,Avdelningen för farmakognosi (author)
Craik, David J.University of Queensland, Institute for Molecular Bioscience (author)
Göransson, UlfUppsala universitet,Institutionen för läkemedelskemi,Avdelningen för farmakognosi(Swepub:uu)ugo29049 (author)
Uppsala universitetInstitutionen för läkemedelskemi (creator_code:org_t)

In:Antioxidants and Redox Signaling: Mary Ann Liebert Inc14:1, s. 77-861523-08641557-7716

By the author/editor: Aboye, Teshome L ...; Clark, Richard J ...; Burman, Robert; Roig, Marta Bajo ...; Craik, David J.; Göransson, Ulf

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmaceutical S ...

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