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

Garton, Michael ; Nim, Satra ; Stone, Tracy A. ; Wang, Kyle Ethan ; Deber, Charles M. ; Kim, Philip M.

Proceedings of the National Academy of Sciences - PNAS, 2018-02, Vol.115 (7), p.1505-1510 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB
Autor: Garton, Michael ; Nim, Satra ; Stone, Tracy A. ; Wang, Kyle Ethan ; Deber, Charles M. ; Kim, Philip M.
Assuntos: Algorithms ; Amino acids ; Amino Acids - chemistry ; Analogs ; Biocompatibility ; Biological Sciences ; Biomedical materials ; Cells ; Data banks ; Databases, Protein ; Diabetes mellitus ; Drug development ; Glucagon-Like Peptide 1 - agonists ; Glucagon-Like Peptide 1 - chemistry ; Glucagon-Like Peptide 1 - metabolism ; Glucagon-Like Peptide-1 Receptor - metabolism ; Half life ; HEK293 Cells ; Humans ; Molecules ; Osteoporosis ; Parathyroid Hormone - agonists ; Parathyroid Hormone - chemistry ; Parathyroid Hormone - metabolism ; Peptides ; Peptides - chemistry ; Peptides - metabolism ; Peptides - pharmacokinetics ; Proteases ; Protein Conformation ; Protein Engineering - methods ; Protein structure ; Proteins ; Receptor, Parathyroid Hormone, Type 1 - metabolism ; Receptors ; Reproducibility of Results
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2018-02, Vol.115 (7), p.1505-1510
Notas: Edited by William F. DeGrado, University of California, San Francisco, CA, and approved December 21, 2017 (received for review July 4, 2017)
Author contributions: M.G., C.M.D., and P.M.K. designed research; M.G., S.N., T.A.S., K.E.W., C.M.D., and P.M.K. performed research; S.N., T.A.S., and C.M.D. contributed new reagents/analytic tools; M.G., S.N., K.E.W., and P.M.K. analyzed data; and M.G. and P.M.K. wrote the paper.
Descrição: 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 10⁵-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.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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

Garton, Michael ; Nim, Satra ; Stone, Tracy A. ; Wang, Kyle Ethan ; Deber, Charles M. ; Kim, Philip M.

United States: National Academy of Sciences

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