TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 6741–6744 Pergamon An amyloid-like fibril forming antiparallel supramolecular -sheet from a synthetic tripeptide: a crystallographic signature Arijit Banerjee, a Samir Kumar Maji, a Michael G. B. Drew, b Debasish Haldar a and Arindam Banerjee a, * a Department of Biological Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta 700 032, India b Department of Chemistry, The University of Reading, Whiteknights, Reading RG66AD, UK Received 2 May 2003; revised 18 June 2003; accepted 27 June 2003 Abstract—Single crystal X-ray diffraction studies of a terminally blocked tripeptide Boc-Leu(1)-Aib(2)-Leu(3)-OMe 1 demon- strates that it adopts a bend structure without any intramolecular hydrogen bond. Peptide 1 self-assembles to form a supramolecular antiparallel -sheet structure by various non-covalent interactions including intermolecular hydrogen bonds in the crystal and it exhibits amyloid-like fibrillar morphology in the solid state. © 2003 Elsevier Ltd. All rights reserved. The design of short model peptide molecules with a suitable conformation, that is able to self-associate via non-covalent interactions, forming supramolecular - sheet architectures is particularly important in biological 1 and material sciences. 2 Zhang and co-work- ers have shown that a self-assembling -sheet peptide scaffold 1a can serve as a substrate for neurite outgrowth and synapse formation and this type of biologically compatible scaffold is also very useful for tissue repair- ing and tissue engineering. Higher order self-association of peptide molecules leads to the formation of fibrils and gels. 3 Understanding the -sheet aggregation of proteins and peptides is very important for discovering pathway(s) and the mechanism(s) of amyloid 4 aggrega- tion that would lead to drug discovery for neurodegen- erative diseases like Alzheimer’s disease 5 and Parkinson’s disease. 6 Recently, much evidence has sug- gested that not only disease-related proteins, but also other non-disease related proteins can be induced to form aggregated -sheet rich amyloid fibrils under appropriate conditions. This suggests that fibril forma- tion is a general property of many unrelated proteins. 7,8 Thorough knowledge of -sheet aggregation is thus important to probe the mechanism of fibrillogenesis. Unfortunately, amyloid fibrils are non-crystalline and insoluble, and are therefore intractable to conventional tools of structural biology including single crystal X-ray diffraction studies. Recently, significant progress has been made in the establishment of fibrillation path- way(s) and ultimately fibril structures. In 1997, Teplow and co-workers 5d and Lansbury et al. 9 reported that the protofibril is one of the key intermediates in amyloid fibril formation. Recently, Kirkitadze et al. have demonstrated that the other early stage intermediate, namely the helical structure, is involved during amyloid fibril formation. 10 Significant progress has been made in the understanding of amyloid fibril structure since the establishment of the solid-state structure of amyloid fibrils from A(1-40) (using NMR methods) by Tycko and co-workers. 11 However, we still need a meticulous understanding of the self-assembly of individual com- ponents (at atomic resolution) which form aggregated -sheet structures that are responsible for amyloid fibril formation. We are actively engaged in developing model peptides, which form supramolecular -sheets in crystals and amyloid-like fibrils 12 in the solid-state. This work will assist the amyloid-studying community to ascertain the key parameters and other residual interactions in atomic resolution that are involved during amyloid fibril formation. It is still a controversial issue whether amyloid fibril formation occurs preferentially via the self-assembly of Keywords : Aib; antiparallel -sheet; amyloid-like fibrils; self-assem- bly. * Corresponding author. Fax: +91-33-24732805; e-mail: bcab@ mahendra.iacs.res.in 0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0040-4039(03)01642-3