D-Amino Acids for Bioactive Peptides

Two peptides were tested to prove the concept: GLP-1 and Parathyroid Hormone. Both (L)- and (D)-peptides were synthesized by Lifetein LLC.

1. GLP-1 is a helical GPCR agonist as a diabetes mellitus and obesity treatment. Hotspot and junction residues are annotated in green and blue, respectively. The authors investigated the ability of (D)-GLP1 peptide to induce activation of GLP1R and compared the response with native (L)-GLP1 peptide. It was found that the D-GLP-1 performed well and was resistant to protease degradation. The retro-inversion (RI) reversing the (D)-peptide sequence was used in the experiment.

D amino acid peptides

Glucagon-Like Peptide 1, GLP – 1 (7 – 36), amide, human: 
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR – NH2

2.  Parathyroid Hormone (PTH) is an FDA-approved treatment for osteoporosis. The (D)-PTH activates PTH1R with potency and efficacy comparable to (L)-PTH. And more than 85% of the (D)-PTH analog is still detectable at six hours.

PTH 1-34: SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF

Conclusion: The D-Protein Data Bank (PDB) can be used to search and find therapeutically active topologies. The D-PDB could be a vital tool for finding stable lead molecules in early-stage drug discovery.

Hot spot residues for receptor binding

Reference: 

Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB