Bifunctional PEGylated Exenatide-Amylinomimetic Hybrids to Treat Metabolic Disorders: An Example of Long-Acting Dual Hormonal Therapeutics
Peptide hybrids (phybrids) comprising covalently linked peptide hormones can leverage independent biological pathways for additive or synergistic metabolic benefits. PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produ...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-11, Vol.56 (22), p.9328-9341 |
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| container_title | Journal of medicinal chemistry |
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| creator | Sun, Chengzao Trevaskis, James L Jodka, Carolyn M Neravetla, Swetha Griffin, Pete Xu, Kui Wang, Yan Parkes, David G Forood, Bruce Ghosh, Soumitra S |
| description | Peptide hybrids (phybrids) comprising covalently linked peptide hormones can leverage independent biological pathways for additive or synergistic metabolic benefits. PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produce long-acting therapeutics with dual pharmacology and enhanced efficacy. Compound 10 is composed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic, davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayed dose-dependent and prolonged efficacy for glucose control and body weight reduction in rodents with superior in vitro and in vivo activities compared to those of a side-chain PEGylated phybrid 6. In diet-induced obese (DIO) rats, the weight-loss efficacy of 10 was similar to that of a combination of PEG-parents 3 and 4. A single dose of 10 elicited sustained body weight reduction in DIO rats for at least 21 days. Compound 10’s terminal half-life of ∼27 h should translate favorably to weekly dosing in humans. |
| doi_str_mv | 10.1021/jm401418s |
| format | Article |
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PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produce long-acting therapeutics with dual pharmacology and enhanced efficacy. Compound 10 is composed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic, davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayed dose-dependent and prolonged efficacy for glucose control and body weight reduction in rodents with superior in vitro and in vivo activities compared to those of a side-chain PEGylated phybrid 6. In diet-induced obese (DIO) rats, the weight-loss efficacy of 10 was similar to that of a combination of PEG-parents 3 and 4. A single dose of 10 elicited sustained body weight reduction in DIO rats for at least 21 days. Compound 10’s terminal half-life of ∼27 h should translate favorably to weekly dosing in humans.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm401418s</identifier><identifier>PMID: 24144329</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Drug Design ; Exenatide ; Female ; Humans ; Islet Amyloid Polypeptide - chemistry ; Male ; Metabolic Diseases - drug therapy ; Mice ; Models, Molecular ; Obesity - drug therapy ; Peptide Hormones - metabolism ; Peptides - chemistry ; Peptides - pharmacokinetics ; Peptides - pharmacology ; Peptides - therapeutic use ; Peptidomimetics - chemistry ; Peptidomimetics - pharmacokinetics ; Peptidomimetics - pharmacology ; Peptidomimetics - therapeutic use ; Polyethylene Glycols - chemistry ; Protein Structure, Secondary ; Rats ; Time Factors ; Venoms - chemistry ; Venoms - pharmacokinetics ; Venoms - pharmacology ; Venoms - therapeutic use</subject><ispartof>Journal of medicinal chemistry, 2013-11, Vol.56 (22), p.9328-9341</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-dab1cdbdcffb124f1fe578e764af5b0bf34c0d24bd99a7c2906094bfd2ddb31a3</citedby><cites>FETCH-LOGICAL-a315t-dab1cdbdcffb124f1fe578e764af5b0bf34c0d24bd99a7c2906094bfd2ddb31a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm401418s$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm401418s$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24144329$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Chengzao</creatorcontrib><creatorcontrib>Trevaskis, James L</creatorcontrib><creatorcontrib>Jodka, Carolyn M</creatorcontrib><creatorcontrib>Neravetla, Swetha</creatorcontrib><creatorcontrib>Griffin, Pete</creatorcontrib><creatorcontrib>Xu, Kui</creatorcontrib><creatorcontrib>Wang, Yan</creatorcontrib><creatorcontrib>Parkes, David G</creatorcontrib><creatorcontrib>Forood, Bruce</creatorcontrib><creatorcontrib>Ghosh, Soumitra S</creatorcontrib><title>Bifunctional PEGylated Exenatide-Amylinomimetic Hybrids to Treat Metabolic Disorders: An Example of Long-Acting Dual Hormonal Therapeutics</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Peptide hybrids (phybrids) comprising covalently linked peptide hormones can leverage independent biological pathways for additive or synergistic metabolic benefits. PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produce long-acting therapeutics with dual pharmacology and enhanced efficacy. Compound 10 is composed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic, davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayed dose-dependent and prolonged efficacy for glucose control and body weight reduction in rodents with superior in vitro and in vivo activities compared to those of a side-chain PEGylated phybrid 6. In diet-induced obese (DIO) rats, the weight-loss efficacy of 10 was similar to that of a combination of PEG-parents 3 and 4. A single dose of 10 elicited sustained body weight reduction in DIO rats for at least 21 days. Compound 10’s terminal half-life of ∼27 h should translate favorably to weekly dosing in humans.</description><subject>Animals</subject><subject>Drug Design</subject><subject>Exenatide</subject><subject>Female</subject><subject>Humans</subject><subject>Islet Amyloid Polypeptide - chemistry</subject><subject>Male</subject><subject>Metabolic Diseases - drug therapy</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Obesity - drug therapy</subject><subject>Peptide Hormones - metabolism</subject><subject>Peptides - chemistry</subject><subject>Peptides - pharmacokinetics</subject><subject>Peptides - pharmacology</subject><subject>Peptides - therapeutic use</subject><subject>Peptidomimetics - chemistry</subject><subject>Peptidomimetics - pharmacokinetics</subject><subject>Peptidomimetics - pharmacology</subject><subject>Peptidomimetics - therapeutic use</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Protein Structure, Secondary</subject><subject>Rats</subject><subject>Time Factors</subject><subject>Venoms - chemistry</subject><subject>Venoms - pharmacokinetics</subject><subject>Venoms - pharmacology</subject><subject>Venoms - therapeutic use</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM1uEzEURi0EoqGw4AWQN0h0McXXdn6GXdqGBimILtL1yD_XxdF4HGyPRF6hT11D2q66uot7dD7pEPIR2DkwDl93QTKQsMivyASmnDVyweRrMmGM84bPuDgh73LeMcYEcPGWnHAJUgreTsj9hXfjYIqPg-rpzer60KuClq7-4qCKt9gsw6H3Qww-YPGGrg86eZtpiXSbUBX6E4vSsa-vK59jspjyN7ocqkGFfY80OrqJw12zrCPDHb0a6846pvB_cPsbk9rjWM35PXnjVJ_xw-M9JbffV9vLdbP5df3jcrlplIBpaazSYKy2xjkNXDpwOJ0vcD6Tyk01005IwyyX2ratmhveshlrpXaWW6sFKHFKvhy9-xT_jJhLF3w22PdqwDjmDmQtNgcBs4qeHVGTYs4JXbdPPqh06IB1_9J3z-kr--lRO-qA9pl8al2Bz0dAmdzt4phqgPyC6AGooI1-</recordid><startdate>20131127</startdate><enddate>20131127</enddate><creator>Sun, Chengzao</creator><creator>Trevaskis, James L</creator><creator>Jodka, Carolyn M</creator><creator>Neravetla, Swetha</creator><creator>Griffin, Pete</creator><creator>Xu, Kui</creator><creator>Wang, Yan</creator><creator>Parkes, David G</creator><creator>Forood, Bruce</creator><creator>Ghosh, Soumitra S</creator><general>American Chemical Society</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>7X8</scope></search><sort><creationdate>20131127</creationdate><title>Bifunctional PEGylated Exenatide-Amylinomimetic Hybrids to Treat Metabolic Disorders: An Example of Long-Acting Dual Hormonal Therapeutics</title><author>Sun, Chengzao ; Trevaskis, James L ; Jodka, Carolyn M ; Neravetla, Swetha ; Griffin, Pete ; Xu, Kui ; Wang, Yan ; Parkes, David G ; Forood, Bruce ; Ghosh, Soumitra S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-dab1cdbdcffb124f1fe578e764af5b0bf34c0d24bd99a7c2906094bfd2ddb31a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Drug Design</topic><topic>Exenatide</topic><topic>Female</topic><topic>Humans</topic><topic>Islet Amyloid Polypeptide - chemistry</topic><topic>Male</topic><topic>Metabolic Diseases - drug therapy</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Obesity - drug therapy</topic><topic>Peptide Hormones - metabolism</topic><topic>Peptides - chemistry</topic><topic>Peptides - pharmacokinetics</topic><topic>Peptides - pharmacology</topic><topic>Peptides - therapeutic use</topic><topic>Peptidomimetics - chemistry</topic><topic>Peptidomimetics - pharmacokinetics</topic><topic>Peptidomimetics - pharmacology</topic><topic>Peptidomimetics - therapeutic use</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Protein Structure, Secondary</topic><topic>Rats</topic><topic>Time Factors</topic><topic>Venoms - chemistry</topic><topic>Venoms - pharmacokinetics</topic><topic>Venoms - pharmacology</topic><topic>Venoms - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Chengzao</creatorcontrib><creatorcontrib>Trevaskis, James L</creatorcontrib><creatorcontrib>Jodka, Carolyn M</creatorcontrib><creatorcontrib>Neravetla, Swetha</creatorcontrib><creatorcontrib>Griffin, Pete</creatorcontrib><creatorcontrib>Xu, Kui</creatorcontrib><creatorcontrib>Wang, Yan</creatorcontrib><creatorcontrib>Parkes, David G</creatorcontrib><creatorcontrib>Forood, Bruce</creatorcontrib><creatorcontrib>Ghosh, Soumitra S</creatorcontrib><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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Chengzao</au><au>Trevaskis, James L</au><au>Jodka, Carolyn M</au><au>Neravetla, Swetha</au><au>Griffin, Pete</au><au>Xu, Kui</au><au>Wang, Yan</au><au>Parkes, David G</au><au>Forood, Bruce</au><au>Ghosh, Soumitra S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bifunctional PEGylated Exenatide-Amylinomimetic Hybrids to Treat Metabolic Disorders: An Example of Long-Acting Dual Hormonal Therapeutics</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-11-27</date><risdate>2013</risdate><volume>56</volume><issue>22</issue><spage>9328</spage><epage>9341</epage><pages>9328-9341</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Peptide hybrids (phybrids) comprising covalently linked peptide hormones can leverage independent biological pathways for additive or synergistic metabolic benefits. PEGylation of biologics offers enhanced stability, duration, and reduced immunogenicity. These two modalities can be combined to produce long-acting therapeutics with dual pharmacology and enhanced efficacy. Compound 10 is composed of an exenatide (AC2993) analogue, AC3174, and an amylinomimetic, davalintide (AC2307), with an intervening 40 kD PEG moiety. It displayed dose-dependent and prolonged efficacy for glucose control and body weight reduction in rodents with superior in vitro and in vivo activities compared to those of a side-chain PEGylated phybrid 6. In diet-induced obese (DIO) rats, the weight-loss efficacy of 10 was similar to that of a combination of PEG-parents 3 and 4. A single dose of 10 elicited sustained body weight reduction in DIO rats for at least 21 days. Compound 10’s terminal half-life of ∼27 h should translate favorably to weekly dosing in humans.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24144329</pmid><doi>10.1021/jm401418s</doi><tpages>14</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2013-11, Vol.56 (22), p.9328-9341 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Drug Design Exenatide Female Humans Islet Amyloid Polypeptide - chemistry Male Metabolic Diseases - drug therapy Mice Models, Molecular Obesity - drug therapy Peptide Hormones - metabolism Peptides - chemistry Peptides - pharmacokinetics Peptides - pharmacology Peptides - therapeutic use Peptidomimetics - chemistry Peptidomimetics - pharmacokinetics Peptidomimetics - pharmacology Peptidomimetics - therapeutic use Polyethylene Glycols - chemistry Protein Structure, Secondary Rats Time Factors Venoms - chemistry Venoms - pharmacokinetics Venoms - pharmacology Venoms - therapeutic use |
| title | Bifunctional PEGylated Exenatide-Amylinomimetic Hybrids to Treat Metabolic Disorders: An Example of Long-Acting Dual Hormonal Therapeutics |
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