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Chemical Synthesis of Maxadilan, a Non-mammalian Potent Vasodilatory Peptide Consisting of 61 Amino Acids with Two Disulfide Bridges, and Its Related Peptides

  • Bruce Merrifield Commemorative Issue
  • Published:
International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

Abstract

A potent and persistent non-mammalian derived vasodilator, maxadilan (Maxa) consists of 61 amino acids with two disulfide linkages and acts as an agonist of the type I receptor of pituitary adenylate cyclase activating polypeptide (PACAP), although there is very little sequence similarity. The total chemical syntheses of Maxa, its disulfide isomers and various fragments have been performed successfully by highly efficient solid-phase peptide synthesis (SPPS). A “difficult sequence”, envisaged in the middle region of Maxa, could be overcome by improved synthesis protocols. After assembly peptides were liberated from the resin by cleavage. Peptides having disulfide(s) were purified by two steps of preparative HPLC using cation exchange followed by reverse phase columns. Purified peptides were characterized by HPLC, Edman-sequencing, amino acid analysis and mass spectrometry in addition to disulfide form determination. The peptides obtained were used for recognition studies by the melanophore assay to confirm the native disulfide form. Peptide libraries related to Maxa, produced in the present study, will be useful for the elucidation of the structural requirements of Maxa for interaction with the PACAP type 1 receptor (PAC1).

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Abbreviations

HATU:

N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide

HOBt:

1-hydroxybenzotriazole

LC-IT-MS:

liquid chromatograph with on-line ion-trap mass spectrometry

MALDI-TOF MS:

matrix assisted laser desorption ionization time of flight mass spectrometry

Maxa:

maxadilan

PACAP:

pituitary adenylate cyclase activating polypeptide

PAC1:

PACAP type 1 receptor

SPPS:

solid-phase peptide synthesis

RP-HPLC:

reverse-phase high performance liquid chromatography

PyBOP:

benzotriazole-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate

TFA:

trifluoroacetic acid

TMP:

2,4,6-trimethylpyridine

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Acknowledgments

The authors thank Professor T. Kasama, Tokyo Medical and Dental University for MALDI-TOF analyses. A part of the present study was supported by a grant from the Ministry of Education, Science, and Culture, Japan.

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Authors and Affiliations

  1. HiPep Laboratories, Nakatsukasa-cho 486-46, Kamigyo-ku, Kyoto, 602-8158, Japan

    Kiyoshi Nokihara

  2. Tokyo University of Agriculture, Tokyo, 156-0054, Japan

    Tadashi Yasuhara

  3. Hiroshima University, Hiroshima, 734-8551, Japan

    Yoshihiro Nakata

  4. Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Ethan A. Lerner

  5. Department of Structural Biology, Helmholtz Centre for Infection Research, D-38124, Braunschweig, Germany

    Victor Wray

Authors
  1. Kiyoshi Nokihara
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  2. Tadashi Yasuhara
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  3. Yoshihiro Nakata
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  4. Ethan A. Lerner
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  5. Victor Wray
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Corresponding author

Correspondence to Kiyoshi Nokihara.

Additional information

This paper is dedicated to the memory of Professor Bruce Merrifield, a pioneer and one of the most respected experimental scientists, who made extraordinary contributions to high throughput chemical synthesis.

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Nokihara, K., Yasuhara, T., Nakata, Y. et al. Chemical Synthesis of Maxadilan, a Non-mammalian Potent Vasodilatory Peptide Consisting of 61 Amino Acids with Two Disulfide Bridges, and Its Related Peptides. Int J Pept Res Ther 13, 377–386 (2007). https://doi.org/10.1007/s10989-007-9097-9

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  • DOI: https://doi.org/10.1007/s10989-007-9097-9

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