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Pregabalin peptides: conformational comparison of γ3- and γ4-substituted γ-amino acids in αγααα pentapeptides

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Abstract

Gamma-aminobutyric acid (GABA, gammaAbu), an unsubstituted gamma-amino acid, is an important inhibitory neurotransmitter in the mammalian brain. The role of GABA in the treatment of epilepsy has triggered a great deal of interest in substituted gamma-amino acids, which may serve as GABA analogs, acting as inhibitors of GABA aminotransferase. Pregabalin (Pgn), a well-known antiepileptic drug, is also a beta-substituted gamma3-amino acid. Pregabalin and gamma4Leu, an isomer of the pregabalin (Pgn) residue, both carrying the same isobutyryl group in the side chain, were introduced in the present study to have a comparison of their respective conformational differences as well as their role in influencing the overall conformation of the peptides, they are inserted in. Two alpha–gamma–alpha–alpha–alpha hybrid pentapeptides were designed that contain Aib-Pgn and Aib-gamma4Leu segments at the N terminus. The study provides a detailed analysis of the conformational properties and non-covalent interactions observed in the crystal structures of two polymorphs of the pentapeptide monohydrate, Boc-Aib-(S)Pgn-Leu-Phe-Val-OMe (C38H63N5O8·H2O) and the isomeric pentapeptide, Boc-Aib-gamma4(R)Leu-Leu-Phe-Val-OMe (C38H63N5O8), obtained from single crystal X-ray diffraction experiments.

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Author notes

  1. Krishnayan Basuroy

    Present address: Photon Science Division, Deutsches Elektronen-Synchrotron (DESY), 22607, Hamburg, Germany

Authors and Affiliations

  1. Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560012, India

    Krishnayan Basuroy, Subrayashastry Aravinda & Padmanabhan Balaram

  2. Department of Chemistry, Rani Channamma University, Belagavi, Vidya Sangama, P B R H-4, Belgaum, 591156, India

    Kamanna Kantharaju

  3. Department of Physics, Indian Institute of Science, Bangalore, 560012, India

    Narayanaswamy Shamala

Authors
  1. Krishnayan Basuroy
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  2. Kamanna Kantharaju
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  3. Subrayashastry Aravinda
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  4. Narayanaswamy Shamala
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  5. Padmanabhan Balaram
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Correspondence to Padmanabhan Balaram.

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For the present study, there were no human or animal participants used as subjects in this study. Therefore, formal consent wass not required.

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Handling Editor: M. S. Palma.

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Basuroy, K., Kantharaju, K., Aravinda, S. et al. Pregabalin peptides: conformational comparison of γ3- and γ4-substituted γ-amino acids in αγααα pentapeptides. Amino Acids 51, 1297–1306 (2019). https://doi.org/10.1007/s00726-019-02768-5

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  • DOI: https://doi.org/10.1007/s00726-019-02768-5

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