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Published on: August 1, 2018
Structure-function relationship studies of PTH(1-11) analogues containing sterically hindered dipeptide mimetics
Nereo Fiori1, Andrea Caporale, Elisabetta Schievano
1Department of Chemical Sciences, Institute of Biomolecular Chemistry, University of Padova, CNR, Italy.
Summary
Researchers developed miniaturized parathyroid hormone (PTH) mimetics using constrained dipeptide units. These novel PTH analogues showed poor biological activity, suggesting specific side-chain orientations are critical for receptor interaction.
Area of Science:
- Medicinal Chemistry
- Peptide Chemistry
- Endocrinology
Background:
- Parathyroid hormone (PTH) N-terminal fragment (1-34) is biologically active.
- Developing non-parenteral PTH-like bone anabolic agents is a therapeutic goal.
- Miniaturized PTH mimetics are explored for safer bone therapies.
Purpose of the Study:
- To synthesize and characterize PTH(1-11) analogues incorporating rigidified dipeptide mimetics.
- To investigate the conformational and biological effects of introducing 7,5-bicyclic thiazolidinlactam (7,5-bTL) into PTH sequences.
- To understand structure-activity relationships for PTH analogue design.
Main Methods:
- Synthesis of three pseudo-undecapeptides containing the 7,5-bTL unit.
- Conformational analysis using Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR).
- Molecular dynamics calculations and in vitro biological activity assays (EC50 determination).
Main Results:
- Analogue I, with 7,5-bTL at positions 3-4, adopted an alpha-helical conformation.
- NMR and molecular dynamics localized the alpha-helix to Ile(5)-His(9) in analogue I.
- All synthesized analogues exhibited poor biological activity (EC50 > 0.1 mM).
Conclusions:
- The 7,5-bTL dipeptide mimetic can induce or stabilize alpha-helical structures in PTH analogues.
- Specific side-chain orientations (Val(2), Ile(5), Met(8)) appear crucial for PTH analogue-receptor binding.
- Future PTH agonist design should focus on incorporating correct amino acid substitutions onto rigid scaffolds.
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