Glyco-scan: varying glycosylation in the sequence of the peptide hormone PYY3-36 and its effect on receptor selectivity

Chembiochem. 2010 Feb 15;11(3):366-74. doi: 10.1002/cbic.200900661.

Abstract

The increasing prevalence of obesity worldwide calls for safe and highly efficacious satiety drugs. PYY3-36 has been implicated in food intake regulation, and novel peptide analogues with high Y2 receptor-subtype selectivity and potency have potential as drugs for the treatment of obesity. It has been hypothesized that PYY3-36 associates with the plasma membrane prior to receptor activation such that the amphipathic alpha-helix of PYY3-36 possibly guides the C-terminal pentapeptide into the correct conformation for receptor activation. Ala-scans are used routinely to study the effect of individual amino acids in a given peptide sequence. Here we report the glyco-scan of the peptide hormone PYY3-36, in which hydroxyl side-chain functionalities were glycosylated; in addition new glycosylation sites were introduced. An array of novel PYY3-36 analogues with a glycan positioned in the water-membrane interface or in the N terminal were screened for Y-receptor affinity and selectivity as well as metabolic stability. Interestingly, in contrast to the Y1 and Y4 receptors, the Y2 receptor readily accommodated glycosylations. Especially glycosylations in the alpha-helical region of PYY3-36 were favorable both in terms of Y-receptor selectivity and endopeptidase resistance. We thus report several PYY3-36 analogues with enhanced Y-receptor selectivity. Our results can be used in the design of novel PYY analogues for the treatment of obesity. The glyco-scan concept, as systematically demonstrated here, has the potential for a wider applicability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circular Dichroism
  • Glycosylation
  • Humans
  • Mice
  • Obesity / drug therapy
  • Peptide Fragments
  • Peptide YY / chemical synthesis
  • Peptide YY / chemistry
  • Peptide YY / metabolism*
  • Protein Structure, Secondary
  • Receptors, Neuropeptide Y / metabolism
  • Structure-Activity Relationship

Substances

  • Peptide Fragments
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor
  • neuropeptide Y2 receptor
  • Peptide YY
  • peptide YY (3-36)
  • neuropeptide Y4 receptor