Designed Beta-Turn Mimic Based on the Allylic-Strain Concept: Evaluation of Structural and Biological Features by Incorporation into a Cyclic RGD Peptide (Cyclo(-L-arginylglycyl-L-α-aspartyl-))
✍ Scribed by Martin Sukopp; Luciana Marinelli; Markus Heller; Trixi Brandl; Simon L. Goodman; Reinhard W. Hoffmann; Horst Kessler
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- German
- Weight
- 144 KB
- Volume
- 85
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
Abstract
The (3__R__,5__S__,6__E__,8__S__,10__R__)‐11‐amino‐3,5,8,10‐tetramethylundec‐6‐enoic acid (ATUA; 1), which was designed as a __β__II′‐turn mimic according to the concepts of allylic strain and 2,4‐dimethylpentane units, was incorporated into a cyclic RGD peptide. The three‐dimensional structure of cyclo(‐RGD‐ATUA‐) (=cyclo(‐Arg‐Gly‐Asp‐ATUA‐)) 4 in H~2~O was determined by NMR techniques, distance geometry calculations and molecular‐dynamics simulations. The RGD sequence of 4 shows high conformational flexibility but some preference for an extended conformation. The structural features of the RGD sequence of 4 were compared with the RGD moiety of cyclo(‐RGDfV‐) (=cyclo(‐Arg‐Gly‐Asp‐D‐Phe‐Val‐)). In contrast to cyclo(‐RGDfV‐), which is a highly active __α__v__β__3 antagonist and selective against __α__IIb__β__3, cyclo(‐RGD‐ATUA‐) shows a lower activity and selectivity. The structure of the ATUA residue in the cyclic peptide resembles a __β__II′‐turn‐like conformation. Its middle part, adjacent to the CC bond, strongly prefers the designed and desired structure.