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Optimized clinical performance of growth hormone with an expanded genetic code.

ABSTRACT: The ribosomal incorporation of nonnative amino acids into polypeptides in living cells provides the opportunity to endow therapeutic proteins with unique pharmacological properties. We report here the first clinical study of a biosynthetic protein produced using an expanded genetic code. Incorporation of p-acetylphenylalanine (pAcF) at distinct locations in human growth hormone (hGH) allowed site-specific conjugation with polyethylene glycol (PEG) to produce homogeneous hGH variants. A mono-PEGylated mutant hGH modified at residue 35 demonstrated favorable pharmacodynamic properties in GH-deficient rats. Clinical studies in GH-deficient adults demonstrated efficacy and safety comparable to native human growth hormone therapy but with increased potency and reduced injection frequency. This example illustrates the utility of nonnative amino acids to optimize protein therapeutics in an analogous fashion to the use of medicinal chemistry to optimize conventional natural products, low molecular weight drugs, and peptides.

SUBMITTER: Cho H

PROVIDER: S-EPMC3107295 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Optimized clinical performance of growth hormone with an expanded genetic code.

Cho Ho H Daniel Tom T Buechler Ying Ji YJ Litzinger David C DC Maio Zhenwei Z Putnam Anna-Maria Hays AM Kraynov Vadim S VS Sim Bee-Cheng BC Bussell Stuart S Javahishvili Tsotne T Kaphle Sami S Viramontes Guillermo G Ong Mike M Chu Stephanie S Becky G C GC Lieu Ricky R Knudsen Nick N Castiglioni Paola P Norman Thea C TC Axelrod Douglas W DW Hoffman Andrew R AR Schultz Peter G PG DiMarchi Richard D RD Kimmel Bruce E BE

Proceedings of the National Academy of Sciences of the United States of America 20110516 22

The ribosomal incorporation of nonnative amino acids into polypeptides in living cells provides the opportunity to endow therapeutic proteins with unique pharmacological properties. We report here the first clinical study of a biosynthetic protein produced using an expanded genetic code. Incorporation of p-acetylphenylalanine (pAcF) at distinct locations in human growth hormone (hGH) allowed site-specific conjugation with polyethylene glycol (PEG) to produce homogeneous hGH variants. A mono-PEGy ...[more]

PMID: 21576502

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Project description:Cardiovascular disease (CVD) has been linked to animal-based diets, which are a major source of trimethylamine (TMA), a precursor of the proatherogenic compound trimethylamine-N-oxide (TMAO). Human gut bacteria in the genus Bilophila have genomic signatures for genetic code expansion that could enable them to metabolize both TMA and its precursors without production of TMAO. We uncovered evidence that the Bilophila demethylation pathway is actively transcribed in gut microbiomes and that animal-based diets cause Bilophila to rapidly increase in abundance. CVD occurrence and Bilophila abundance in humans were significantly negatively correlated. These data lead us to propose that Bilophila, which is commonly regarded as a pathobiont, may play a role in mitigating cardiovascular disease. Human gut microbiomes have been shown to affect the development of a myriad of disease states, but mechanistic connections between diet, health, and microbiota have been challenging to establish. The hypothesis that Bilophila reduces cardiovascular disease by circumventing TMAO production offers a clearly defined mechanism with a potential human health impact, but investigations of Bilophila cell biology and ecology will be needed to fully evaluate these ideas.IMPORTANCE Links between trimethylamine-N-oxide (TMAO) and cardiovascular disease (CVD) have focused attention on mechanisms by which animal-based diets have negative health consequences. In a meta-analysis of data from foundational gut microbiome studies, we found evidence that specialized bacteria have and express a metabolic pathway that circumvents TMAO production and is often misannotated because it relies on genetic code expansion. This naturally occurring mechanism for TMAO attenuation is negatively correlated with CVD. Ultimately, these findings point to new avenues of research that could increase microbiome-informed understanding of human health and hint at potential biomedical applications in which specialized bacteria are used to curtail CVD development.

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Optimized clinical performance of growth hormone with an expanded genetic code.

Publications

Optimized clinical performance of growth hormone with an expanded genetic code.

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