Optimised approach to albumin-drug conjugates using monobromomaleimide-C-2 linkers
Conjugation of therapeutics to human serum albumin (HSA) using bromomaleimides represents a promising platform for half-life extension. We show here that the Cys-34 crevice substantially reduces the rate of serum stabilising maleimide hydrolysis in these conjugates, necessitating reagent optimisatio...
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| Veröffentlicht in: | Organic & biomolecular chemistry 2019-08, Vol.17 (34), p.787-7873 |
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| container_title | Organic & biomolecular chemistry |
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| creator | Wall, Archie Nicholls, Karl Caspersen, Mikael B Skrivergaard, Stig Howard, Kenneth A Karu, Kersti Chudasama, Vijay Baker, James R |
| description | Conjugation of therapeutics to human serum albumin (HSA) using bromomaleimides represents a promising platform for half-life extension. We show here that the Cys-34 crevice substantially reduces the rate of serum stabilising maleimide hydrolysis in these conjugates, necessitating reagent optimisation. This improved reagent design is applied to the construction of an HSA-paclitaxel conjugate, preventing drug loss during maleimide hydrolysis.
Monobromomaleimides with C-2-PEG linkers offer an optimised platform for site-selective albumin conjugation, offering efficient conjugation and accelerated stabilising hydrolysis which prevents loss of drug during construction. |
| doi_str_mv | 10.1039/c9ob00721k |
| format | Article |
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Monobromomaleimides with C-2-PEG linkers offer an optimised platform for site-selective albumin conjugation, offering efficient conjugation and accelerated stabilising hydrolysis which prevents loss of drug during construction.</description><identifier>ISSN: 1477-0520</identifier><identifier>EISSN: 1477-0539</identifier><identifier>DOI: 10.1039/c9ob00721k</identifier><identifier>PMID: 31410415</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Albumin ; Albumins ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - toxicity ; Cell Line, Tumor ; Conjugates ; Conjugation ; Cysteine - chemistry ; Design optimization ; Drug development ; Drug Stability ; Human serum albumin ; Humans ; Hydrolysis ; Life extension ; Maleimides - chemistry ; Maleimides - toxicity ; Paclitaxel ; Paclitaxel - analogs & derivatives ; Paclitaxel - toxicity ; Reagents ; Serum albumin ; Serum Albumin, Human - chemistry ; Serum Albumin, Human - toxicity</subject><ispartof>Organic & biomolecular chemistry, 2019-08, Vol.17 (34), p.787-7873</ispartof><rights>Copyright Royal Society of Chemistry 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c373t-cca5c7eabccdeb21dff34f8c23f43d09a1b42a6d283832217511b8b72673b1983</citedby><cites>FETCH-LOGICAL-c373t-cca5c7eabccdeb21dff34f8c23f43d09a1b42a6d283832217511b8b72673b1983</cites><orcidid>0000-0002-8876-3285 ; 0000-0002-7223-2279</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31410415$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wall, Archie</creatorcontrib><creatorcontrib>Nicholls, Karl</creatorcontrib><creatorcontrib>Caspersen, Mikael B</creatorcontrib><creatorcontrib>Skrivergaard, Stig</creatorcontrib><creatorcontrib>Howard, Kenneth A</creatorcontrib><creatorcontrib>Karu, Kersti</creatorcontrib><creatorcontrib>Chudasama, Vijay</creatorcontrib><creatorcontrib>Baker, James R</creatorcontrib><title>Optimised approach to albumin-drug conjugates using monobromomaleimide-C-2 linkers</title><title>Organic & biomolecular chemistry</title><addtitle>Org Biomol Chem</addtitle><description>Conjugation of therapeutics to human serum albumin (HSA) using bromomaleimides represents a promising platform for half-life extension. We show here that the Cys-34 crevice substantially reduces the rate of serum stabilising maleimide hydrolysis in these conjugates, necessitating reagent optimisation. This improved reagent design is applied to the construction of an HSA-paclitaxel conjugate, preventing drug loss during maleimide hydrolysis.
Monobromomaleimides with C-2-PEG linkers offer an optimised platform for site-selective albumin conjugation, offering efficient conjugation and accelerated stabilising hydrolysis which prevents loss of drug during construction.</description><subject>Albumin</subject><subject>Albumins</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Cell Line, Tumor</subject><subject>Conjugates</subject><subject>Conjugation</subject><subject>Cysteine - chemistry</subject><subject>Design optimization</subject><subject>Drug development</subject><subject>Drug Stability</subject><subject>Human serum albumin</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Life extension</subject><subject>Maleimides - chemistry</subject><subject>Maleimides - toxicity</subject><subject>Paclitaxel</subject><subject>Paclitaxel - analogs & derivatives</subject><subject>Paclitaxel - toxicity</subject><subject>Reagents</subject><subject>Serum albumin</subject><subject>Serum Albumin, Human - chemistry</subject><subject>Serum Albumin, Human - toxicity</subject><issn>1477-0520</issn><issn>1477-0539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0U1LxDAQBuAgiqurF-9KwYsI1UzSNu1Ri1-4sCB6Lvnq2t22qUlz8N8b3XUFTwnkmWHmDUIngK8A0-JaFkZgzAisdtABJIzFOKXF7vZO8AQdOrfEGAqWJftoQiEBnEB6gF7mw9h0jdMq4sNgDZfv0Wgi3grfNX2srF9E0vRLv-CjdpF3Tb-IOtMbYU1nOt7qUK10XMYkapt-pa07Qns1b50-3pxT9HZ_91o-xrP5w1N5M4slZXSMpeSpZJoLKZUWBFRd06TOJaF1QhUuOIiE8EyRnOaUEGApgMgFIxmjAoqcTtHFum8Y-8NrN1ZhD6nblvfaeFcRwiiBLOwf6Pk_ujTe9mG6oHKCMxISC-pyraQ1zlldV4NtOm4_K8DVd9JVWcxvf5J-Dvhs09KLTqst_Y02gNM1sE5uX_--in4BtOqCWw</recordid><startdate>20190828</startdate><enddate>20190828</enddate><creator>Wall, Archie</creator><creator>Nicholls, Karl</creator><creator>Caspersen, Mikael B</creator><creator>Skrivergaard, Stig</creator><creator>Howard, Kenneth A</creator><creator>Karu, Kersti</creator><creator>Chudasama, Vijay</creator><creator>Baker, James R</creator><general>Royal Society of Chemistry</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>7QO</scope><scope>7T7</scope><scope>7TM</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8876-3285</orcidid><orcidid>https://orcid.org/0000-0002-7223-2279</orcidid></search><sort><creationdate>20190828</creationdate><title>Optimised approach to albumin-drug conjugates using monobromomaleimide-C-2 linkers</title><author>Wall, Archie ; Nicholls, Karl ; Caspersen, Mikael B ; Skrivergaard, Stig ; Howard, Kenneth A ; Karu, Kersti ; Chudasama, Vijay ; Baker, James R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c373t-cca5c7eabccdeb21dff34f8c23f43d09a1b42a6d283832217511b8b72673b1983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Albumin</topic><topic>Albumins</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - toxicity</topic><topic>Cell Line, Tumor</topic><topic>Conjugates</topic><topic>Conjugation</topic><topic>Cysteine - chemistry</topic><topic>Design optimization</topic><topic>Drug development</topic><topic>Drug Stability</topic><topic>Human serum albumin</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>Life extension</topic><topic>Maleimides - chemistry</topic><topic>Maleimides - toxicity</topic><topic>Paclitaxel</topic><topic>Paclitaxel - analogs & derivatives</topic><topic>Paclitaxel - toxicity</topic><topic>Reagents</topic><topic>Serum albumin</topic><topic>Serum Albumin, Human - chemistry</topic><topic>Serum Albumin, Human - toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wall, Archie</creatorcontrib><creatorcontrib>Nicholls, Karl</creatorcontrib><creatorcontrib>Caspersen, Mikael B</creatorcontrib><creatorcontrib>Skrivergaard, Stig</creatorcontrib><creatorcontrib>Howard, Kenneth A</creatorcontrib><creatorcontrib>Karu, Kersti</creatorcontrib><creatorcontrib>Chudasama, Vijay</creatorcontrib><creatorcontrib>Baker, James R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Organic & biomolecular chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wall, Archie</au><au>Nicholls, Karl</au><au>Caspersen, Mikael B</au><au>Skrivergaard, Stig</au><au>Howard, Kenneth A</au><au>Karu, Kersti</au><au>Chudasama, Vijay</au><au>Baker, James R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimised approach to albumin-drug conjugates using monobromomaleimide-C-2 linkers</atitle><jtitle>Organic & biomolecular chemistry</jtitle><addtitle>Org Biomol Chem</addtitle><date>2019-08-28</date><risdate>2019</risdate><volume>17</volume><issue>34</issue><spage>787</spage><epage>7873</epage><pages>787-7873</pages><issn>1477-0520</issn><eissn>1477-0539</eissn><abstract>Conjugation of therapeutics to human serum albumin (HSA) using bromomaleimides represents a promising platform for half-life extension. We show here that the Cys-34 crevice substantially reduces the rate of serum stabilising maleimide hydrolysis in these conjugates, necessitating reagent optimisation. This improved reagent design is applied to the construction of an HSA-paclitaxel conjugate, preventing drug loss during maleimide hydrolysis.
Monobromomaleimides with C-2-PEG linkers offer an optimised platform for site-selective albumin conjugation, offering efficient conjugation and accelerated stabilising hydrolysis which prevents loss of drug during construction.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>31410415</pmid><doi>10.1039/c9ob00721k</doi><tpages>4</tpages><orcidid>https://orcid.org/0000-0002-8876-3285</orcidid><orcidid>https://orcid.org/0000-0002-7223-2279</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Royal Society Of Chemistry Journals; Alma/SFX Local Collection |
| subjects | Albumin Albumins Antineoplastic Agents - chemistry Antineoplastic Agents - toxicity Cell Line, Tumor Conjugates Conjugation Cysteine - chemistry Design optimization Drug development Drug Stability Human serum albumin Humans Hydrolysis Life extension Maleimides - chemistry Maleimides - toxicity Paclitaxel Paclitaxel - analogs & derivatives Paclitaxel - toxicity Reagents Serum albumin Serum Albumin, Human - chemistry Serum Albumin, Human - toxicity |
| title | Optimised approach to albumin-drug conjugates using monobromomaleimide-C-2 linkers |
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