Gramicidin S Derivatives Containing cis‐ and trans‐Morpholine Amino Acids (MAAs) as Turn Mimetics |
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| Authors: | Varsha V. Kapoerchan Dr. Emile Spalburg Albert. J. de Neeling Dr. Roos H. Mars‐Groenendijk Daan Noort Dr. José M. Otero Patricia Ferraces‐Casais Dr. Antonio L. Llamas‐Saiz Dr. Mark J. van Raaij Dr. Joop van Doorn Dr. Gijs A. van der Marel Prof. Dr. Herman S. Overkleeft Prof. Dr. Mark Overhand Dr. |
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| Affiliation: | 1. Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands);2. Laboratory for Infectious Diseases, National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven (The Netherlands);3. Defense, Security and SafetyTNO, P.O. Box 45, 2280 AA Rijswijk (The Netherlands);4. Departamento de Bioquímica y Biología Molecular, Faculta de Farmacia Campus Sur, Universidad de Santiago de Compostela, 15782 Santiago de Compostela (Spain);5. Unidad de Rayos X (RIAIDT), Laboratorio Integral de dinámica y Estructura de Biomoléculas “José R. Carracido”, Edificio CACTUS, Campus Sur, Universidad de Santiago de Compostela, 15782 Santiago de Compostela (Spain);6. Departamento de Biología Estructural, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Baldiri Reixac 10, 08028 Barcelona (Spain);7. Applied Plant Research, P.O. Box 85, 2160 AB Lisse (The Netherlands) |
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| Abstract: | ![]()
The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D ‐Phe‐Pro two‐residue turn motifs in the rigid cyclic β‐hairpin structure of GS was replaced with morpholine amino acids (MAA 2 – 5 ), differing in stereochemistry and length of the side‐chain. The conformational properties of the thus obtained GS analogues ( 6 – 9 ) was assessed by using NMR spectroscopy and X‐ray crystallography, and correlated with their biological properties (antimicrobial and hemolytic activity). We show that compound 8 , containing the dipeptide isostere trans‐MAA 4 , has an apparent high structural resemblance with GS and that its antibacterial activity against a panel of Gram positive and ‐negative bacterial strains is better than the derivatives 6 , 7 and 9 . |
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| Keywords: | antibiotics conformation analysis gramicidin S peptides peptidomimetics |
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