PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn
Peptides targeting the human neonatal Fc receptor (FcRn) were conjugated to poly(ethylene glycol) (PEG) polymers to study their effect on inhibition of the IgG:FcRn protein–protein interaction both in vitro and in mice. Both linear (5–40 kDa) and branched (20, 40 kDa) PEG aldehydes were conjugated t...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (21), p.6332-6335 |
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| creator | Mezo, Adam R. Low, Susan C. Hoehn, Todd Palmieri, Holly |
| description | Peptides targeting the human neonatal Fc receptor (FcRn) were conjugated to poly(ethylene glycol) (PEG) polymers to study their effect on inhibition of the IgG:FcRn protein–protein interaction both in vitro and in mice. Both linear (5–40
kDa) and branched (20, 40
kDa) PEG aldehydes were conjugated to an amine-containing linker of a homodimeric anti-FcRn peptide using reductive alkylation chemistry. It was found that conjugation of PEG to the peptide compromised the in vitro activity, with larger and branched PEGs causing the most dramatic losses in activity. The conjugates were evaluated in transgenic mice for their ability to accelerate the catabolism of human IgG. Optimal pharmacodynamic properties were observed with PEG–peptide conjugates that contained 20–40
kDa linear PEGs and a 20
kDa branched PEG. The optimal PEG–peptide conjugates were more effective in vivo than the unconjugated peptide control on a mole:mole and mg/kg basis, and represent potential new longer-acting peptide therapeutics for the treatment of humorally-mediated autoimmune disease. |
| doi_str_mv | 10.1016/j.bmcl.2011.08.111 |
| format | Article |
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kDa) and branched (20, 40
kDa) PEG aldehydes were conjugated to an amine-containing linker of a homodimeric anti-FcRn peptide using reductive alkylation chemistry. It was found that conjugation of PEG to the peptide compromised the in vitro activity, with larger and branched PEGs causing the most dramatic losses in activity. The conjugates were evaluated in transgenic mice for their ability to accelerate the catabolism of human IgG. Optimal pharmacodynamic properties were observed with PEG–peptide conjugates that contained 20–40
kDa linear PEGs and a 20
kDa branched PEG. The optimal PEG–peptide conjugates were more effective in vivo than the unconjugated peptide control on a mole:mole and mg/kg basis, and represent potential new longer-acting peptide therapeutics for the treatment of humorally-mediated autoimmune disease.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.08.111</identifier><identifier>PMID: 21920737</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>aldehydes ; alkylation ; Animals ; antagonists ; Autoimmune disease ; Biological and medical sciences ; Electrophoresis, Polyacrylamide Gel ; Enzyme-Linked Immunosorbent Assay ; FcRn inhibitor ; Humans ; immunoglobulin G ; Immunoglobulin G - metabolism ; Immunomodulators ; Medical sciences ; metabolism ; Mice ; Mice, Transgenic ; Neonatal Fc receptor ; PEGylation ; peptides ; Peptides - antagonists & inhibitors ; Peptides - pharmacology ; Pharmacology. Drug treatments ; polyethylene glycol ; Polyethylene Glycols - chemistry ; protein-protein interactions ; Receptors, Fc - antagonists & inhibitors ; Receptors, Fc - metabolism ; therapeutics ; transgenic animals</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-11, Vol.21 (21), p.6332-6335</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-eaf9c622ac59a227b25ca63fc7f2599f6c32dc2d1e052aef484bd2e5e46a5c663</citedby><cites>FETCH-LOGICAL-c441t-eaf9c622ac59a227b25ca63fc7f2599f6c32dc2d1e052aef484bd2e5e46a5c663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11012108$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24698230$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21920737$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mezo, Adam R.</creatorcontrib><creatorcontrib>Low, Susan C.</creatorcontrib><creatorcontrib>Hoehn, Todd</creatorcontrib><creatorcontrib>Palmieri, Holly</creatorcontrib><title>PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Peptides targeting the human neonatal Fc receptor (FcRn) were conjugated to poly(ethylene glycol) (PEG) polymers to study their effect on inhibition of the IgG:FcRn protein–protein interaction both in vitro and in mice. Both linear (5–40
kDa) and branched (20, 40
kDa) PEG aldehydes were conjugated to an amine-containing linker of a homodimeric anti-FcRn peptide using reductive alkylation chemistry. It was found that conjugation of PEG to the peptide compromised the in vitro activity, with larger and branched PEGs causing the most dramatic losses in activity. The conjugates were evaluated in transgenic mice for their ability to accelerate the catabolism of human IgG. Optimal pharmacodynamic properties were observed with PEG–peptide conjugates that contained 20–40
kDa linear PEGs and a 20
kDa branched PEG. The optimal PEG–peptide conjugates were more effective in vivo than the unconjugated peptide control on a mole:mole and mg/kg basis, and represent potential new longer-acting peptide therapeutics for the treatment of humorally-mediated autoimmune disease.</description><subject>aldehydes</subject><subject>alkylation</subject><subject>Animals</subject><subject>antagonists</subject><subject>Autoimmune disease</subject><subject>Biological and medical sciences</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>FcRn inhibitor</subject><subject>Humans</subject><subject>immunoglobulin G</subject><subject>Immunoglobulin G - metabolism</subject><subject>Immunomodulators</subject><subject>Medical sciences</subject><subject>metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neonatal Fc receptor</subject><subject>PEGylation</subject><subject>peptides</subject><subject>Peptides - antagonists & inhibitors</subject><subject>Peptides - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>polyethylene glycol</subject><subject>Polyethylene Glycols - chemistry</subject><subject>protein-protein interactions</subject><subject>Receptors, Fc - antagonists & inhibitors</subject><subject>Receptors, Fc - metabolism</subject><subject>therapeutics</subject><subject>transgenic animals</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFrFDEUx4Modlv9Ah50LtKLMyaZJDsDXqS0VSgoasFbeJt5abPMTsYkK_Tb-4Zd9SYeQkj4veS9_4-xF4I3ggvzdttsdm5sJBei4V0jhHjEVkIZVbeK68dsxXvD665X30_Yac5bzoXiSj1lJ1L0kq_b9Yr5z5fXDyOUEKcKp3uYHOaq3OOyEsy4L8FVcyw4lQBjFX0141zCgBVMBe7iFHLJy_VSM2GcoBB25aqEjsCY3tDhy_SMPfEwZnx-3M_Y7dXlt4sP9c2n648X729qp5QoNYLvnZESnO5ByvVGagem9W7tpe57b1wrBycHgVxLQK86tRkkalQGtDOmPWPnh3fnFH_sMRe7C9nhOAL1ts-2p_n7Tnf6f0jKtTWKSHkgXYo5J_R2TmEH6cEKbhcRdmsXEXYRYXlnSQQVvTw-v9_scPhT8jt5Al4fAcgORp8o-pD_csr0nWw5ca8OnIdo4S4Rc_uVftJks9U0DRHvDgRSsD8DJptdQBI5BJJQ7BDDvzr9BWovsGw</recordid><startdate>20111101</startdate><enddate>20111101</enddate><creator>Mezo, Adam R.</creator><creator>Low, Susan C.</creator><creator>Hoehn, Todd</creator><creator>Palmieri, Holly</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20111101</creationdate><title>PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn</title><author>Mezo, Adam R. ; Low, Susan C. ; Hoehn, Todd ; Palmieri, Holly</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-eaf9c622ac59a227b25ca63fc7f2599f6c32dc2d1e052aef484bd2e5e46a5c663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>aldehydes</topic><topic>alkylation</topic><topic>Animals</topic><topic>antagonists</topic><topic>Autoimmune disease</topic><topic>Biological and medical sciences</topic><topic>Electrophoresis, Polyacrylamide Gel</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>FcRn inhibitor</topic><topic>Humans</topic><topic>immunoglobulin G</topic><topic>Immunoglobulin G - metabolism</topic><topic>Immunomodulators</topic><topic>Medical sciences</topic><topic>metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neonatal Fc receptor</topic><topic>PEGylation</topic><topic>peptides</topic><topic>Peptides - antagonists & inhibitors</topic><topic>Peptides - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>polyethylene glycol</topic><topic>Polyethylene Glycols - chemistry</topic><topic>protein-protein interactions</topic><topic>Receptors, Fc - antagonists & inhibitors</topic><topic>Receptors, Fc - metabolism</topic><topic>therapeutics</topic><topic>transgenic animals</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mezo, Adam R.</creatorcontrib><creatorcontrib>Low, Susan C.</creatorcontrib><creatorcontrib>Hoehn, Todd</creatorcontrib><creatorcontrib>Palmieri, Holly</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mezo, Adam R.</au><au>Low, Susan C.</au><au>Hoehn, Todd</au><au>Palmieri, Holly</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-11-01</date><risdate>2011</risdate><volume>21</volume><issue>21</issue><spage>6332</spage><epage>6335</epage><pages>6332-6335</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Peptides targeting the human neonatal Fc receptor (FcRn) were conjugated to poly(ethylene glycol) (PEG) polymers to study their effect on inhibition of the IgG:FcRn protein–protein interaction both in vitro and in mice. Both linear (5–40
kDa) and branched (20, 40
kDa) PEG aldehydes were conjugated to an amine-containing linker of a homodimeric anti-FcRn peptide using reductive alkylation chemistry. It was found that conjugation of PEG to the peptide compromised the in vitro activity, with larger and branched PEGs causing the most dramatic losses in activity. The conjugates were evaluated in transgenic mice for their ability to accelerate the catabolism of human IgG. Optimal pharmacodynamic properties were observed with PEG–peptide conjugates that contained 20–40
kDa linear PEGs and a 20
kDa branched PEG. The optimal PEG–peptide conjugates were more effective in vivo than the unconjugated peptide control on a mole:mole and mg/kg basis, and represent potential new longer-acting peptide therapeutics for the treatment of humorally-mediated autoimmune disease.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21920737</pmid><doi>10.1016/j.bmcl.2011.08.111</doi><tpages>4</tpages></addata></record> |
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| subjects | aldehydes alkylation Animals antagonists Autoimmune disease Biological and medical sciences Electrophoresis, Polyacrylamide Gel Enzyme-Linked Immunosorbent Assay FcRn inhibitor Humans immunoglobulin G Immunoglobulin G - metabolism Immunomodulators Medical sciences metabolism Mice Mice, Transgenic Neonatal Fc receptor PEGylation peptides Peptides - antagonists & inhibitors Peptides - pharmacology Pharmacology. Drug treatments polyethylene glycol Polyethylene Glycols - chemistry protein-protein interactions Receptors, Fc - antagonists & inhibitors Receptors, Fc - metabolism therapeutics transgenic animals |
| title | PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn |
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