Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity
The incidence of fatal overdoses has increased worldwide due to the widespread access to illicit fentanyl and its potent analogues. Vaccines offer a promising strategy to reduce the prevalence of opioid use disorders (OUDs) and to prevent toxicity from accidental and deliberate exposure to fentanyl...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-12, Vol.63 (23), p.14647-14667 |
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| container_title | Journal of medicinal chemistry |
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| creator | Robinson, Christine Gradinati, Valeria Hamid, Fatima Baehr, Carly Crouse, Bethany Averick, Saadyah Kovaliov, Marina Harris, Danni Runyon, Scott Baruffaldi, Federico LeSage, Mark Comer, Sandra Pravetoni, Marco |
| description | The incidence of fatal overdoses has increased worldwide due to the widespread access to illicit fentanyl and its potent analogues. Vaccines offer a promising strategy to reduce the prevalence of opioid use disorders (OUDs) and to prevent toxicity from accidental and deliberate exposure to fentanyl and its derivatives. This study describes the development and characterization of vaccine formulations consisting of novel fentanyl-based haptens conjugated to carrier proteins. Vaccine efficacy was tested against opioid-induced behavior and toxicity in mice and rats challenged with fentanyl and its analogues. Prophylactic vaccination reduced fentanyl- and sufentanil-induced antinociception, respiratory depression, and bradycardia in mice and rats. Therapeutic vaccination also reduced fentanyl intravenous self-administration in rats. Because of their selectivity, vaccines did not interfere with the pharmacological effects of commonly used anesthetics nor with methadone, naloxone, oxycodone, or heroin. These preclinical data support the translation of vaccines as a viable strategy to counteract fentanyl use disorders and toxicity. |
| doi_str_mv | 10.1021/acs.jmedchem.0c01042 |
| format | Article |
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Vaccines offer a promising strategy to reduce the prevalence of opioid use disorders (OUDs) and to prevent toxicity from accidental and deliberate exposure to fentanyl and its derivatives. This study describes the development and characterization of vaccine formulations consisting of novel fentanyl-based haptens conjugated to carrier proteins. Vaccine efficacy was tested against opioid-induced behavior and toxicity in mice and rats challenged with fentanyl and its analogues. Prophylactic vaccination reduced fentanyl- and sufentanil-induced antinociception, respiratory depression, and bradycardia in mice and rats. Therapeutic vaccination also reduced fentanyl intravenous self-administration in rats. Because of their selectivity, vaccines did not interfere with the pharmacological effects of commonly used anesthetics nor with methadone, naloxone, oxycodone, or heroin. These preclinical data support the translation of vaccines as a viable strategy to counteract fentanyl use disorders and toxicity.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01042</identifier><identifier>PMID: 33215913</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Bacterial Proteins - chemistry ; Bacterial Proteins - immunology ; Cattle ; Diphtheria Toxin - chemistry ; Diphtheria Toxin - immunology ; Female ; Fentanyl - immunology ; Haptens - chemistry ; Haptens - immunology ; Hemocyanins - chemistry ; Hemocyanins - immunology ; Male ; Mice, Inbred BALB C ; Opioid-Related Disorders - prevention & control ; Opioid-Related Disorders - therapy ; Piperidines - chemical synthesis ; Piperidines - immunology ; Proof of Concept Study ; Rats, Sprague-Dawley ; Serum Albumin, Bovine - chemistry ; Serum Albumin, Bovine - immunology ; Sufentanil - immunology ; Vaccines - immunology</subject><ispartof>Journal of medicinal chemistry, 2020-12, Vol.63 (23), p.14647-14667</ispartof><rights>2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-1797dfaeadd23250ffd866639c7ba168e1159ab98d6e046f670d1a0327c554ec3</citedby><cites>FETCH-LOGICAL-a449t-1797dfaeadd23250ffd866639c7ba168e1159ab98d6e046f670d1a0327c554ec3</cites><orcidid>0000-0002-8259-1267 ; 0000-0003-4775-2317 ; 0000-0003-1036-0184</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c01042$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01042$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33215913$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Robinson, Christine</creatorcontrib><creatorcontrib>Gradinati, Valeria</creatorcontrib><creatorcontrib>Hamid, Fatima</creatorcontrib><creatorcontrib>Baehr, Carly</creatorcontrib><creatorcontrib>Crouse, Bethany</creatorcontrib><creatorcontrib>Averick, Saadyah</creatorcontrib><creatorcontrib>Kovaliov, Marina</creatorcontrib><creatorcontrib>Harris, Danni</creatorcontrib><creatorcontrib>Runyon, Scott</creatorcontrib><creatorcontrib>Baruffaldi, Federico</creatorcontrib><creatorcontrib>LeSage, Mark</creatorcontrib><creatorcontrib>Comer, Sandra</creatorcontrib><creatorcontrib>Pravetoni, Marco</creatorcontrib><title>Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The incidence of fatal overdoses has increased worldwide due to the widespread access to illicit fentanyl and its potent analogues. Vaccines offer a promising strategy to reduce the prevalence of opioid use disorders (OUDs) and to prevent toxicity from accidental and deliberate exposure to fentanyl and its derivatives. This study describes the development and characterization of vaccine formulations consisting of novel fentanyl-based haptens conjugated to carrier proteins. Vaccine efficacy was tested against opioid-induced behavior and toxicity in mice and rats challenged with fentanyl and its analogues. Prophylactic vaccination reduced fentanyl- and sufentanil-induced antinociception, respiratory depression, and bradycardia in mice and rats. Therapeutic vaccination also reduced fentanyl intravenous self-administration in rats. Because of their selectivity, vaccines did not interfere with the pharmacological effects of commonly used anesthetics nor with methadone, naloxone, oxycodone, or heroin. These preclinical data support the translation of vaccines as a viable strategy to counteract fentanyl use disorders and toxicity.</description><subject>Animals</subject><subject>Bacterial Proteins - chemistry</subject><subject>Bacterial Proteins - immunology</subject><subject>Cattle</subject><subject>Diphtheria Toxin - chemistry</subject><subject>Diphtheria Toxin - immunology</subject><subject>Female</subject><subject>Fentanyl - immunology</subject><subject>Haptens - chemistry</subject><subject>Haptens - immunology</subject><subject>Hemocyanins - chemistry</subject><subject>Hemocyanins - immunology</subject><subject>Male</subject><subject>Mice, Inbred BALB C</subject><subject>Opioid-Related Disorders - prevention & control</subject><subject>Opioid-Related Disorders - therapy</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - immunology</subject><subject>Proof of Concept Study</subject><subject>Rats, Sprague-Dawley</subject><subject>Serum Albumin, Bovine - chemistry</subject><subject>Serum Albumin, Bovine - immunology</subject><subject>Sufentanil - immunology</subject><subject>Vaccines - immunology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kF1LwzAUhoMobk7_gUj_QOdJ0qbtjSDTqTDQi00vQ5akNqNrStKK_fd2n-iNV4GT93nP4UHoGsMYA8G3Qvrxaq2VLPR6DBIwROQEDXFMIIxSiE7REICQkDBCB-jC-xUAUEzoORpQSnCcYTpEH_NCO1HrtjEyEJUK3pyti64UcjN4F1KaSvugscHEtlXTZ2UTTHXViKorg4XXwYPx1int_Baf228jTdNdorNclF5f7d8RWkwf55PncPb69DK5n4UiirImxEmWqFxooRShJIY8VyljjGYyWQrMUo37O8UySxXTELGcJaCwAEoSGceRlnSE7na9dbvcyOgvc6LktTNr4TpuheF_fypT8E_7xVOcUZayviDaFUhnvXc6P7IY-EY070Xzg2i-F91jN7_3HqGD2T4Au8AWt62reg3_d_4Ae4qPzA</recordid><startdate>20201210</startdate><enddate>20201210</enddate><creator>Robinson, Christine</creator><creator>Gradinati, Valeria</creator><creator>Hamid, Fatima</creator><creator>Baehr, Carly</creator><creator>Crouse, Bethany</creator><creator>Averick, Saadyah</creator><creator>Kovaliov, Marina</creator><creator>Harris, Danni</creator><creator>Runyon, Scott</creator><creator>Baruffaldi, Federico</creator><creator>LeSage, Mark</creator><creator>Comer, Sandra</creator><creator>Pravetoni, Marco</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>5PM</scope><orcidid>https://orcid.org/0000-0002-8259-1267</orcidid><orcidid>https://orcid.org/0000-0003-4775-2317</orcidid><orcidid>https://orcid.org/0000-0003-1036-0184</orcidid></search><sort><creationdate>20201210</creationdate><title>Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity</title><author>Robinson, Christine ; Gradinati, Valeria ; Hamid, Fatima ; Baehr, Carly ; Crouse, Bethany ; Averick, Saadyah ; Kovaliov, Marina ; Harris, Danni ; Runyon, Scott ; Baruffaldi, Federico ; LeSage, Mark ; Comer, Sandra ; Pravetoni, Marco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-1797dfaeadd23250ffd866639c7ba168e1159ab98d6e046f670d1a0327c554ec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Bacterial Proteins - chemistry</topic><topic>Bacterial Proteins - immunology</topic><topic>Cattle</topic><topic>Diphtheria Toxin - chemistry</topic><topic>Diphtheria Toxin - immunology</topic><topic>Female</topic><topic>Fentanyl - immunology</topic><topic>Haptens - chemistry</topic><topic>Haptens - immunology</topic><topic>Hemocyanins - chemistry</topic><topic>Hemocyanins - immunology</topic><topic>Male</topic><topic>Mice, Inbred BALB C</topic><topic>Opioid-Related Disorders - prevention & control</topic><topic>Opioid-Related Disorders - therapy</topic><topic>Piperidines - chemical synthesis</topic><topic>Piperidines - immunology</topic><topic>Proof of Concept Study</topic><topic>Rats, Sprague-Dawley</topic><topic>Serum Albumin, Bovine - chemistry</topic><topic>Serum Albumin, Bovine - immunology</topic><topic>Sufentanil - immunology</topic><topic>Vaccines - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Robinson, Christine</creatorcontrib><creatorcontrib>Gradinati, Valeria</creatorcontrib><creatorcontrib>Hamid, Fatima</creatorcontrib><creatorcontrib>Baehr, Carly</creatorcontrib><creatorcontrib>Crouse, Bethany</creatorcontrib><creatorcontrib>Averick, Saadyah</creatorcontrib><creatorcontrib>Kovaliov, Marina</creatorcontrib><creatorcontrib>Harris, Danni</creatorcontrib><creatorcontrib>Runyon, Scott</creatorcontrib><creatorcontrib>Baruffaldi, Federico</creatorcontrib><creatorcontrib>LeSage, Mark</creatorcontrib><creatorcontrib>Comer, Sandra</creatorcontrib><creatorcontrib>Pravetoni, Marco</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robinson, Christine</au><au>Gradinati, Valeria</au><au>Hamid, Fatima</au><au>Baehr, Carly</au><au>Crouse, Bethany</au><au>Averick, Saadyah</au><au>Kovaliov, Marina</au><au>Harris, Danni</au><au>Runyon, Scott</au><au>Baruffaldi, Federico</au><au>LeSage, Mark</au><au>Comer, Sandra</au><au>Pravetoni, Marco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| ispartof | Journal of medicinal chemistry, 2020-12, Vol.63 (23), p.14647-14667 |
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| subjects | Animals Bacterial Proteins - chemistry Bacterial Proteins - immunology Cattle Diphtheria Toxin - chemistry Diphtheria Toxin - immunology Female Fentanyl - immunology Haptens - chemistry Haptens - immunology Hemocyanins - chemistry Hemocyanins - immunology Male Mice, Inbred BALB C Opioid-Related Disorders - prevention & control Opioid-Related Disorders - therapy Piperidines - chemical synthesis Piperidines - immunology Proof of Concept Study Rats, Sprague-Dawley Serum Albumin, Bovine - chemistry Serum Albumin, Bovine - immunology Sufentanil - immunology Vaccines - immunology |
| title | Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity |
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