Optimized clinical performance of growth hormone with an expanded genetic code
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. Incorporati...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-05, Vol.108 (22), p.9060-9065 |
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| creator | Cho, Ho Daniel, Tom Buechler, Ying Ji Litzinger, David C Maio, Zhenwei Putnam, Anna-Maria Hays Kraynov, Vadim S Sim, Bee-Cheng Bussell, Stuart Javahishvili, Tsotne Kaphle, Sami Viramontes, Guillermo Ong, Mike Chu, Stephanie GC, Becky Lieu, Ricky Knudsen, Nick Castiglioni, Paola Norman, Thea C Axelrod, Douglas W Hoffman, Andrew R Schultz, Peter G DiMarchi, Richard D Kimmel, Bruce E |
| description | 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. |
| doi_str_mv | 10.1073/pnas.1100387108 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1100387108</identifier><identifier>PMID: 21576502</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>adults ; Amino acids ; Animals ; Biological Sciences ; biopharmaceuticals ; Body weight ; Cells ; clinical trials ; Dosage ; Dose-Response Relationship, Drug ; Drugs ; Endocrinology - methods ; Genetic code ; Genetic Variation ; Genetics ; Growth hormone ; Growth hormones ; hormone replacement therapy ; human growth ; Human Growth Hormone - genetics ; Human Growth Hormone - pharmacology ; Humans ; Male ; Medical treatment ; medicinal properties ; molecular weight ; mutants ; Mutation ; natural products ; Peptides ; Peptides - chemistry ; Pharmacodynamics ; Pharmacokinetics ; Phenylalanine - analogs & derivatives ; Phenylalanine - chemistry ; Placebos ; Polyethylene glycol ; Polyethylene Glycols - chemistry ; Polymers - chemistry ; polypeptides ; Protein Engineering - methods ; Protein synthesis ; Rats ; Rats, Sprague-Dawley ; Ribosomes - chemistry ; Rodents ; somatotropin ; Tibia</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-05, Vol.108 (22), p.9060-9065</ispartof><rights>Copyright National Academy of Sciences May 31, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c521t-658034ba8c6c73bcb4a242b7d27e9208d54717e91699768a5b8a725eca028ff53</citedby><cites>FETCH-LOGICAL-c521t-658034ba8c6c73bcb4a242b7d27e9208d54717e91699768a5b8a725eca028ff53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/22.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25831087$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25831087$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21576502$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cho, Ho</creatorcontrib><creatorcontrib>Daniel, Tom</creatorcontrib><creatorcontrib>Buechler, Ying Ji</creatorcontrib><creatorcontrib>Litzinger, David C</creatorcontrib><creatorcontrib>Maio, Zhenwei</creatorcontrib><creatorcontrib>Putnam, Anna-Maria Hays</creatorcontrib><creatorcontrib>Kraynov, Vadim S</creatorcontrib><creatorcontrib>Sim, Bee-Cheng</creatorcontrib><creatorcontrib>Bussell, Stuart</creatorcontrib><creatorcontrib>Javahishvili, Tsotne</creatorcontrib><creatorcontrib>Kaphle, Sami</creatorcontrib><creatorcontrib>Viramontes, Guillermo</creatorcontrib><creatorcontrib>Ong, Mike</creatorcontrib><creatorcontrib>Chu, Stephanie</creatorcontrib><creatorcontrib>GC, Becky</creatorcontrib><creatorcontrib>Lieu, Ricky</creatorcontrib><creatorcontrib>Knudsen, Nick</creatorcontrib><creatorcontrib>Castiglioni, Paola</creatorcontrib><creatorcontrib>Norman, Thea C</creatorcontrib><creatorcontrib>Axelrod, Douglas W</creatorcontrib><creatorcontrib>Hoffman, Andrew R</creatorcontrib><creatorcontrib>Schultz, Peter G</creatorcontrib><creatorcontrib>DiMarchi, Richard D</creatorcontrib><creatorcontrib>Kimmel, Bruce E</creatorcontrib><title>Optimized clinical performance of growth hormone with an expanded genetic code</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>adults</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>biopharmaceuticals</subject><subject>Body weight</subject><subject>Cells</subject><subject>clinical trials</subject><subject>Dosage</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drugs</subject><subject>Endocrinology - methods</subject><subject>Genetic code</subject><subject>Genetic Variation</subject><subject>Genetics</subject><subject>Growth hormone</subject><subject>Growth hormones</subject><subject>hormone replacement therapy</subject><subject>human growth</subject><subject>Human Growth Hormone - genetics</subject><subject>Human Growth Hormone - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>Medical treatment</subject><subject>medicinal properties</subject><subject>molecular weight</subject><subject>mutants</subject><subject>Mutation</subject><subject>natural products</subject><subject>Peptides</subject><subject>Peptides - chemistry</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Phenylalanine - analogs & derivatives</subject><subject>Phenylalanine - chemistry</subject><subject>Placebos</subject><subject>Polyethylene glycol</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Polymers - chemistry</subject><subject>polypeptides</subject><subject>Protein Engineering - methods</subject><subject>Protein synthesis</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Ribosomes - chemistry</subject><subject>Rodents</subject><subject>somatotropin</subject><subject>Tibia</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1P3DAQxS1UVBbaM6e2ERdOgbETf12QKkQBCcGBcrYcx9n1KrFTO1ta_vp6tQvb9mR7_JunefMQOsZwhoFX56PX6QxjgEpwDGIPzTBIXLJawjs0AyC8FDWpD9BhSksAkFTAe3RAMOWMApmh-4dxcoN7sW1heued0X0x2tiFOGhvbBG6Yh7D87QoFrkUvC2eXX5oX9hfo_Zt7ptbbydnChNa-wHtd7pP9uP2PEJP366-X96Udw_Xt5df70pDCZ5Klseo6kYLwwyvGtPUmtSk4S3hVhIQLa05zlfMpORMaNoIzQm1RgMRXUerI3Sx0R1XzWBbY_0Uda_G6AYdf6ugnfr3x7uFmoefqsprI3ItcLoViOHHyqZJDS4Z2_fa27BKSjKBGUjGM3nyH7kMq-izOyXyeJhmJkPnG8jEkFK03dsoGNQ6KbVOSu2Syh2f_3bwxr9Gk4EvW2DduZMTihAlgUEmPm2IZZpC3ClQkV0KvlPodFB6Hl1ST48Esi_AMi8Bqj_OAKyB</recordid><startdate>20110531</startdate><enddate>20110531</enddate><creator>Cho, Ho</creator><creator>Daniel, Tom</creator><creator>Buechler, Ying Ji</creator><creator>Litzinger, David C</creator><creator>Maio, Zhenwei</creator><creator>Putnam, Anna-Maria Hays</creator><creator>Kraynov, Vadim S</creator><creator>Sim, Bee-Cheng</creator><creator>Bussell, Stuart</creator><creator>Javahishvili, Tsotne</creator><creator>Kaphle, Sami</creator><creator>Viramontes, Guillermo</creator><creator>Ong, Mike</creator><creator>Chu, Stephanie</creator><creator>GC, Becky</creator><creator>Lieu, Ricky</creator><creator>Knudsen, Nick</creator><creator>Castiglioni, Paola</creator><creator>Norman, Thea C</creator><creator>Axelrod, Douglas W</creator><creator>Hoffman, Andrew R</creator><creator>Schultz, Peter G</creator><creator>DiMarchi, Richard D</creator><creator>Kimmel, Bruce E</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20110531</creationdate><title>Optimized clinical performance of growth hormone with an expanded genetic code</title><author>Cho, Ho ; Daniel, Tom ; Buechler, Ying Ji ; Litzinger, David C ; Maio, Zhenwei ; Putnam, Anna-Maria Hays ; Kraynov, Vadim S ; Sim, Bee-Cheng ; Bussell, Stuart ; Javahishvili, Tsotne ; Kaphle, Sami ; Viramontes, Guillermo ; Ong, Mike ; Chu, Stephanie ; GC, Becky ; Lieu, Ricky ; Knudsen, Nick ; Castiglioni, Paola ; Norman, Thea C ; Axelrod, Douglas W ; Hoffman, Andrew R ; Schultz, Peter G ; DiMarchi, Richard D ; Kimmel, Bruce E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c521t-658034ba8c6c73bcb4a242b7d27e9208d54717e91699768a5b8a725eca028ff53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>adults</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>biopharmaceuticals</topic><topic>Body weight</topic><topic>Cells</topic><topic>clinical trials</topic><topic>Dosage</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drugs</topic><topic>Endocrinology - methods</topic><topic>Genetic code</topic><topic>Genetic Variation</topic><topic>Genetics</topic><topic>Growth hormone</topic><topic>Growth hormones</topic><topic>hormone replacement therapy</topic><topic>human growth</topic><topic>Human Growth Hormone - genetics</topic><topic>Human Growth Hormone - pharmacology</topic><topic>Humans</topic><topic>Male</topic><topic>Medical treatment</topic><topic>medicinal properties</topic><topic>molecular weight</topic><topic>mutants</topic><topic>Mutation</topic><topic>natural products</topic><topic>Peptides</topic><topic>Peptides - chemistry</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Phenylalanine - analogs & derivatives</topic><topic>Phenylalanine - chemistry</topic><topic>Placebos</topic><topic>Polyethylene glycol</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Polymers - chemistry</topic><topic>polypeptides</topic><topic>Protein Engineering - methods</topic><topic>Protein synthesis</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Ribosomes - chemistry</topic><topic>Rodents</topic><topic>somatotropin</topic><topic>Tibia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cho, Ho</creatorcontrib><creatorcontrib>Daniel, Tom</creatorcontrib><creatorcontrib>Buechler, Ying Ji</creatorcontrib><creatorcontrib>Litzinger, David C</creatorcontrib><creatorcontrib>Maio, Zhenwei</creatorcontrib><creatorcontrib>Putnam, Anna-Maria Hays</creatorcontrib><creatorcontrib>Kraynov, Vadim S</creatorcontrib><creatorcontrib>Sim, Bee-Cheng</creatorcontrib><creatorcontrib>Bussell, Stuart</creatorcontrib><creatorcontrib>Javahishvili, Tsotne</creatorcontrib><creatorcontrib>Kaphle, Sami</creatorcontrib><creatorcontrib>Viramontes, Guillermo</creatorcontrib><creatorcontrib>Ong, Mike</creatorcontrib><creatorcontrib>Chu, Stephanie</creatorcontrib><creatorcontrib>GC, Becky</creatorcontrib><creatorcontrib>Lieu, Ricky</creatorcontrib><creatorcontrib>Knudsen, Nick</creatorcontrib><creatorcontrib>Castiglioni, Paola</creatorcontrib><creatorcontrib>Norman, Thea C</creatorcontrib><creatorcontrib>Axelrod, Douglas W</creatorcontrib><creatorcontrib>Hoffman, Andrew R</creatorcontrib><creatorcontrib>Schultz, Peter G</creatorcontrib><creatorcontrib>DiMarchi, Richard D</creatorcontrib><creatorcontrib>Kimmel, Bruce E</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cho, Ho</au><au>Daniel, Tom</au><au>Buechler, Ying Ji</au><au>Litzinger, David C</au><au>Maio, Zhenwei</au><au>Putnam, Anna-Maria Hays</au><au>Kraynov, Vadim S</au><au>Sim, Bee-Cheng</au><au>Bussell, Stuart</au><au>Javahishvili, Tsotne</au><au>Kaphle, Sami</au><au>Viramontes, Guillermo</au><au>Ong, Mike</au><au>Chu, Stephanie</au><au>GC, Becky</au><au>Lieu, Ricky</au><au>Knudsen, Nick</au><au>Castiglioni, Paola</au><au>Norman, Thea C</au><au>Axelrod, Douglas W</au><au>Hoffman, Andrew R</au><au>Schultz, Peter G</au><au>DiMarchi, Richard D</au><au>Kimmel, Bruce E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimized clinical performance of growth hormone with an expanded genetic code</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2011-05-31</date><risdate>2011</risdate><volume>108</volume><issue>22</issue><spage>9060</spage><epage>9065</epage><pages>9060-9065</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21576502</pmid><doi>10.1073/pnas.1100387108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | adults Amino acids Animals Biological Sciences biopharmaceuticals Body weight Cells clinical trials Dosage Dose-Response Relationship, Drug Drugs Endocrinology - methods Genetic code Genetic Variation Genetics Growth hormone Growth hormones hormone replacement therapy human growth Human Growth Hormone - genetics Human Growth Hormone - pharmacology Humans Male Medical treatment medicinal properties molecular weight mutants Mutation natural products Peptides Peptides - chemistry Pharmacodynamics Pharmacokinetics Phenylalanine - analogs & derivatives Phenylalanine - chemistry Placebos Polyethylene glycol Polyethylene Glycols - chemistry Polymers - chemistry polypeptides Protein Engineering - methods Protein synthesis Rats Rats, Sprague-Dawley Ribosomes - chemistry Rodents somatotropin Tibia |
| title | Optimized clinical performance of growth hormone with an expanded genetic code |
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