Metalated peptide fibers derived from a natural metal-binding peptide motif Surajit Ghosh and Sandeep Verma * Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, UP, India Received 28 November 2006; revised 10 January 2007; accepted 17 January 2007 Available online 23 January 2007 Abstract—Biological molecules serve as convenient scaffolds for the construction of nanoscopic architectures which can effectively interact with small molecules and metal complexes to extend their scope for nano(bio)technological applications. Metalloproteins possess natural metal ion binding motifs and the possibility of using these sequences to generate metalated peptide conjugates with defined metal ion coordination offers a facile entry into metalated supramolecular aggregates. This report describes the formation of metalated fibers from Cu-binding octarepeat motifs of the prion protein. Conjugate 1 effectively binds copper, silver, and manga- nese, leading to persistent length and thermally stable peptide fibers, which could be applied for molecular bioelectronic applications. Ó 2007 Elsevier Ltd. All rights reserved. Proteins and peptides possess tremendous potential as useful building blocks for self-assembly owing to their defined secondary and tertiary structures and propensity to interact with the help of various non-covalent inter- actions. These naturally occurring motifs allow rapid access to an array of three-dimensional structures and various side chain functionalities present in constituent amino acids allow further fine-tuning of properties gov- erning the self-assembly process. 1–6 Self-assembling proteins and synthetic peptides are convenient systems for nanotechnology and nano(bio)- technology applications due to the availability of reproducible scale-up synthetic methodologies and the ease of functionalisation of fibrous aggregates with groups that can favorably interact with small molecules, metal ions, and inorganics. 7–9 In this context, it is inter- esting to explore naturally occurring metal binding pep- tide segments for self-assembly to obtain peptide fibers possessing high affinity for metal ion interactions. Mammalian and yeast prions are self-propagating pro- teins rich in b-sheet structure which are held responsible for the etiology of transmissible spongiform encephalo- pathies such as scrapie in sheeps, bovine spongiform encephalopathy in cattle, and Creutzfeldt-Jakob disease in humans. 10–12 Cellular prion protein (PrP C ) is a cupro- glycoprotein whose conformational transition to its infectious, aberrant isoform results in catastrophic cognitive dysfunction in a hallmark of neurological spongiform encephalopathies. 13 Interestingly, PrP C contains an evolutionary conserved stretch of octapep- tide repeats (PHGGGWGQ) that selectively bind Cu 2+ ions with high affinity. Other metal ions also bind to this octarepeat albeit with lower affinity compared to copper. We have previously demonstrated aggregation in trun- cated prion octarepeats. 14,15 The purpose of this study was to gain facile access to peptide fiber formation from prion octapeptide fragments and to extend this strategy to construct metalated fibers from naturally occurring metal binding motifs. Herein, we report the synthesis of a novel bis-peptide conjugate 1, its interaction with 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.01.089 * Corresponding author. Tel.: +91 512 259 7643; fax: +91 512 259 7436; e-mail: sverma@iitk.ac.in N H H N N H O O H N O N NH N H O N H H N N H O O O HO H N O N HN N O H N O O M n+ Conjugate 1 2 3 4 Scheme 1. Molecular structure of conjugates 1–4. Tetrahedron Letters 48 (2007) 2189–2192