A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol
As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in...
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| Veröffentlicht in: | PloS one 2011-06, Vol.6 (6), p.e20669 |
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| creator | Huang, Zhifeng Wang, Huiyan Lu, Meifei Sun, Chuanchuan Wu, Xiaoping Tan, Yi Ye, Chaohui Zhu, Guanghui Wang, Xiaojie Cai, Lu Li, Xiaokun |
| description | As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients. |
| doi_str_mv | 10.1371/journal.pone.0020669 |
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In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0020669</identifier><identifier>PMID: 21673953</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3T3-L1 Cells ; Aldehydes - chemistry ; Analysis ; Animals ; Anion exchanging ; Anion-exchange chromatography ; Antidiabetics ; Asian Americans ; Biology ; Blood glucose ; Blood Glucose - metabolism ; Butyraldehyde ; Cancer ; Cholesterol ; Chromatography ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - blood ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Drug Stability ; Elongation ; Female ; Fibroblast growth factor ; Fibroblast growth factors ; Fibroblast Growth Factors - chemistry ; Fibroblast Growth Factors - pharmacokinetics ; Fibroblast Growth Factors - pharmacology ; Fibroblast Growth Factors - therapeutic use ; Fibroblasts ; Glucose ; Glucose metabolism ; Growth factors ; Health aspects ; Homogeneity ; Humans ; Hypoglycemic agents ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - pharmacokinetics ; Hypoglycemic Agents - pharmacology ; Hypoglycemic Agents - therapeutic use ; Immunogenicity ; Immunology ; Immunotherapy ; Insulin ; Laboratories ; Lipid Metabolism - drug effects ; Male ; Mass spectrometry ; Mass spectroscopy ; Medicine ; Metabolic disorders ; Metabolic syndrome ; Metabolism ; Mice ; Molecular weight ; N-Terminus ; Obesity ; Pediatrics ; Peptides ; Pharmacy ; Physiological aspects ; Polyethylene ; Polyethylene glycol ; Polyethylene Glycols - chemistry ; Protein structure ; Proteins ; Rats ; Recombinant ; Recombinant Proteins - chemistry ; Recombinant Proteins - pharmacokinetics ; Recombinant Proteins - pharmacology ; Recombinant Proteins - therapeutic use ; Secondary structure ; Spinal cord ; Structure-Activity Relationship ; Type 2 diabetes</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e20669</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Huang et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-3ce10eb08446d0dbec62a765eac17411152fa26fdf88bfac7657f3f47602773f3</citedby><cites>FETCH-LOGICAL-c592t-3ce10eb08446d0dbec62a765eac17411152fa26fdf88bfac7657f3f47602773f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108960/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108960/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21673953$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Zhifeng</creatorcontrib><creatorcontrib>Wang, Huiyan</creatorcontrib><creatorcontrib>Lu, Meifei</creatorcontrib><creatorcontrib>Sun, Chuanchuan</creatorcontrib><creatorcontrib>Wu, Xiaoping</creatorcontrib><creatorcontrib>Tan, Yi</creatorcontrib><creatorcontrib>Ye, Chaohui</creatorcontrib><creatorcontrib>Zhu, Guanghui</creatorcontrib><creatorcontrib>Wang, Xiaojie</creatorcontrib><creatorcontrib>Cai, Lu</creatorcontrib><creatorcontrib>Li, Xiaokun</creatorcontrib><title>A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients.</description><subject>3T3-L1 Cells</subject><subject>Aldehydes - chemistry</subject><subject>Analysis</subject><subject>Animals</subject><subject>Anion exchanging</subject><subject>Anion-exchange chromatography</subject><subject>Antidiabetics</subject><subject>Asian Americans</subject><subject>Biology</subject><subject>Blood glucose</subject><subject>Blood Glucose - metabolism</subject><subject>Butyraldehyde</subject><subject>Cancer</subject><subject>Cholesterol</subject><subject>Chromatography</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - blood</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Drug Stability</subject><subject>Elongation</subject><subject>Female</subject><subject>Fibroblast growth factor</subject><subject>Fibroblast growth factors</subject><subject>Fibroblast Growth Factors - chemistry</subject><subject>Fibroblast Growth Factors - pharmacokinetics</subject><subject>Fibroblast Growth Factors - pharmacology</subject><subject>Fibroblast Growth Factors - therapeutic use</subject><subject>Fibroblasts</subject><subject>Glucose</subject><subject>Glucose metabolism</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>Homogeneity</subject><subject>Humans</subject><subject>Hypoglycemic agents</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - pharmacokinetics</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Hypoglycemic Agents - therapeutic use</subject><subject>Immunogenicity</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Insulin</subject><subject>Laboratories</subject><subject>Lipid Metabolism - drug effects</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Medicine</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Molecular weight</subject><subject>N-Terminus</subject><subject>Obesity</subject><subject>Pediatrics</subject><subject>Peptides</subject><subject>Pharmacy</subject><subject>Physiological aspects</subject><subject>Polyethylene</subject><subject>Polyethylene glycol</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Rats</subject><subject>Recombinant</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - pharmacokinetics</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>Secondary structure</subject><subject>Spinal cord</subject><subject>Structure-Activity Relationship</subject><subject>Type 2 diabetes</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uk1v1DAUjBCIlsI_QGCJCxyy-CNxnAvSqmJLpUpc4GzZznPiVRIvtpdq_z1eNq26EsgH2-_NjMdPUxRvCV4R1pDPW78PsxpXOz_DCmOKOW-fFZekZbTkFLPnT84XxasYtxjXTHD-srighDesrdllsVsjDSlBQGpOruycyldnUADjJ-3mXEXDflIzsk4Hr0cVE-qDv08DssokHxAl6GMYNjcbSj6hyXfOOujQvcuInR8PkIbDCDOgfjwYP74uXlg1Rniz7FfFz83XH9ffyrvvN7fX67vS1C1NJTNAMGgsqop3uNNgOFUNr0EZ0lSEkJpaRbntrBA6G8mtxjJbNRzTpmGWXRXvT7q70Ue5DCtKwnAlWowJzojbE6Lzait3wU0qHKRXTv4t-NBLFfIsRpBEES1wRbDidQWWtFpYUzfZjGlrDSJrfVle2-sJOgNzCmo8Ez3vzG6Qvf8tGcGi5UczHxaB4H_tIab_WF5Qvcqu3Gx9FjOTi0au89eFELw9olb_QOXVweRMjot1uX5GqE4EE3yMAeyjcYLlMWwPZuQxbHIJW6a9e_rpR9JDutgfTHXSaQ</recordid><startdate>20110606</startdate><enddate>20110606</enddate><creator>Huang, Zhifeng</creator><creator>Wang, Huiyan</creator><creator>Lu, Meifei</creator><creator>Sun, Chuanchuan</creator><creator>Wu, Xiaoping</creator><creator>Tan, Yi</creator><creator>Ye, Chaohui</creator><creator>Zhu, Guanghui</creator><creator>Wang, Xiaojie</creator><creator>Cai, Lu</creator><creator>Li, Xiaokun</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110606</creationdate><title>A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol</title><author>Huang, Zhifeng ; Wang, Huiyan ; Lu, Meifei ; Sun, Chuanchuan ; Wu, Xiaoping ; Tan, Yi ; Ye, Chaohui ; Zhu, Guanghui ; Wang, Xiaojie ; Cai, Lu ; Li, Xiaokun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-3ce10eb08446d0dbec62a765eac17411152fa26fdf88bfac7657f3f47602773f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>3T3-L1 Cells</topic><topic>Aldehydes - 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pharmacokinetics</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>Secondary structure</topic><topic>Spinal cord</topic><topic>Structure-Activity Relationship</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Zhifeng</creatorcontrib><creatorcontrib>Wang, Huiyan</creatorcontrib><creatorcontrib>Lu, Meifei</creatorcontrib><creatorcontrib>Sun, Chuanchuan</creatorcontrib><creatorcontrib>Wu, Xiaoping</creatorcontrib><creatorcontrib>Tan, Yi</creatorcontrib><creatorcontrib>Ye, Chaohui</creatorcontrib><creatorcontrib>Zhu, Guanghui</creatorcontrib><creatorcontrib>Wang, Xiaojie</creatorcontrib><creatorcontrib>Cai, Lu</creatorcontrib><creatorcontrib>Li, Xiaokun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection (ProQuest)</collection><collection>Natural Science Collection (ProQuest)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Zhifeng</au><au>Wang, Huiyan</au><au>Lu, Meifei</au><au>Sun, Chuanchuan</au><au>Wu, Xiaoping</au><au>Tan, Yi</au><au>Ye, Chaohui</au><au>Zhu, Guanghui</au><au>Wang, Xiaojie</au><au>Cai, Lu</au><au>Li, Xiaokun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-06-06</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e20669</spage><pages>e20669-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21673953</pmid><doi>10.1371/journal.pone.0020669</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-06, Vol.6 (6), p.e20669 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1304890010 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 3T3-L1 Cells Aldehydes - chemistry Analysis Animals Anion exchanging Anion-exchange chromatography Antidiabetics Asian Americans Biology Blood glucose Blood Glucose - metabolism Butyraldehyde Cancer Cholesterol Chromatography Diabetes Diabetes mellitus Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Drug Stability Elongation Female Fibroblast growth factor Fibroblast growth factors Fibroblast Growth Factors - chemistry Fibroblast Growth Factors - pharmacokinetics Fibroblast Growth Factors - pharmacology Fibroblast Growth Factors - therapeutic use Fibroblasts Glucose Glucose metabolism Growth factors Health aspects Homogeneity Humans Hypoglycemic agents Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacokinetics Hypoglycemic Agents - pharmacology Hypoglycemic Agents - therapeutic use Immunogenicity Immunology Immunotherapy Insulin Laboratories Lipid Metabolism - drug effects Male Mass spectrometry Mass spectroscopy Medicine Metabolic disorders Metabolic syndrome Metabolism Mice Molecular weight N-Terminus Obesity Pediatrics Peptides Pharmacy Physiological aspects Polyethylene Polyethylene glycol Polyethylene Glycols - chemistry Protein structure Proteins Rats Recombinant Recombinant Proteins - chemistry Recombinant Proteins - pharmacokinetics Recombinant Proteins - pharmacology Recombinant Proteins - therapeutic use Secondary structure Spinal cord Structure-Activity Relationship Type 2 diabetes |
| title | A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol |
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