Advertisement

 

 

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

Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB.
Author Information (click to view)

Garton M, Nim S, Stone TA, Wang KE, Deber CM, Kim PM,


Garton M, Nim S, Stone TA, Wang KE, Deber CM, Kim PM, (click to view)

Garton M, Nim S, Stone TA, Wang KE, Deber CM, Kim PM,

Advertisement

Proceedings of the National Academy of Sciences of the United States of America 2018 01 29115(7) 1505-1510 doi 10.1073/pnas.1711837115
Abstract

Biologics are a rapidly growing class of therapeutics with many advantages over traditional small molecule drugs. A major obstacle to their development is that proteins and peptides are easily destroyed by proteases and, thus, typically have prohibitively short half-lives in human gut, plasma, and cells. One of the most effective ways to prevent degradation is to engineer analogs from dextrorotary (D)-amino acids, with up to 10-fold improvements in potency reported. We here propose a general peptide-engineering platform that overcomes limitations of previous methods. By creating a mirror image of every structure in the Protein Data Bank (PDB), we generate a database of ∼2.8 million D-peptides. To obtain a D-analog of a given peptide, we search the (D)-PDB for similar configurations of its critical-"hotspot"-residues. As a proof of concept, we apply our method to two peptides that are Food and Drug Administration approved as therapeutics for diabetes and osteoporosis, respectively. We obtain D-analogs that activate the GLP1 and PTH1 receptors with the same efficacy as their natural counterparts and show greatly increased half-life.

Submit a Comment

Your email address will not be published. Required fields are marked *

nineteen − 2 =

[ HIDE/SHOW ]