Deshkanwar S. Brar , Arshpreet Kaur , Madhuri T. Patil , Yoshikazu Honda-Okubo , Nikolai Petrovsky , Deepak B. Salunke
{"title":"简化水溶性收费样受体 2 激动脂肽佐剂的规模化合成,用于基于蛋白质的病毒疫苗","authors":"Deshkanwar S. Brar , Arshpreet Kaur , Madhuri T. Patil , Yoshikazu Honda-Okubo , Nikolai Petrovsky , Deepak B. Salunke","doi":"10.1016/j.bioorg.2024.107835","DOIUrl":null,"url":null,"abstract":"<div><div>Toll-like receptors (TLRs) form a key bridge between the innate and adaptive immune systems. The lipopeptide based TLR2 agonists such as Pam<sub>2</sub>CSK<sub>4</sub> are promising vaccine adjuvants but drawbacks include its surfactant like nature and cumbersome synthesis. Although the TLR2 activity of Pam<sub>2</sub>CS-OMe is commensurate with Pam<sub>2</sub>CSK<sub>4</sub>, its water solubility is much less, rendering it ineffective for clinical use. In the present investigation, we designed a synthesis pathway for a novel water-soluble TLR2-active analogue, Pam<sub>2</sub>CS-DMAPA (<strong>13</strong>), which enhanced the immunogenicity of recombinant SARS-CoV2 and hepatitis B antigens in mice. Co-formulation of compound <strong>13</strong> with 2 % aluminium hydroxide gel led to a further significant improvement in vaccine immunogenicity. This synthetically simpler compound <strong>13</strong> was water soluble and equally potent to Pam<sub>2</sub>CSK<sub>4</sub> adjuvant, but was superior in terms of manufacturing simplicity and scalability. This makes compound <strong>13</strong> a promising TLR2 targeted adjuvant for further development.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"Article 107835"},"PeriodicalIF":4.5000,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Simplified scalable synthesis of a water-soluble toll-like receptor 2 agonistic lipopeptide adjuvant for use with protein-based viral vaccines\",\"authors\":\"Deshkanwar S. Brar , Arshpreet Kaur , Madhuri T. Patil , Yoshikazu Honda-Okubo , Nikolai Petrovsky , Deepak B. Salunke\",\"doi\":\"10.1016/j.bioorg.2024.107835\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Toll-like receptors (TLRs) form a key bridge between the innate and adaptive immune systems. The lipopeptide based TLR2 agonists such as Pam<sub>2</sub>CSK<sub>4</sub> are promising vaccine adjuvants but drawbacks include its surfactant like nature and cumbersome synthesis. Although the TLR2 activity of Pam<sub>2</sub>CS-OMe is commensurate with Pam<sub>2</sub>CSK<sub>4</sub>, its water solubility is much less, rendering it ineffective for clinical use. In the present investigation, we designed a synthesis pathway for a novel water-soluble TLR2-active analogue, Pam<sub>2</sub>CS-DMAPA (<strong>13</strong>), which enhanced the immunogenicity of recombinant SARS-CoV2 and hepatitis B antigens in mice. Co-formulation of compound <strong>13</strong> with 2 % aluminium hydroxide gel led to a further significant improvement in vaccine immunogenicity. This synthetically simpler compound <strong>13</strong> was water soluble and equally potent to Pam<sub>2</sub>CSK<sub>4</sub> adjuvant, but was superior in terms of manufacturing simplicity and scalability. This makes compound <strong>13</strong> a promising TLR2 targeted adjuvant for further development.</div></div>\",\"PeriodicalId\":257,\"journal\":{\"name\":\"Bioorganic Chemistry\",\"volume\":\"153 \",\"pages\":\"Article 107835\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-09-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0045206824007405\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824007405","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Simplified scalable synthesis of a water-soluble toll-like receptor 2 agonistic lipopeptide adjuvant for use with protein-based viral vaccines
Toll-like receptors (TLRs) form a key bridge between the innate and adaptive immune systems. The lipopeptide based TLR2 agonists such as Pam2CSK4 are promising vaccine adjuvants but drawbacks include its surfactant like nature and cumbersome synthesis. Although the TLR2 activity of Pam2CS-OMe is commensurate with Pam2CSK4, its water solubility is much less, rendering it ineffective for clinical use. In the present investigation, we designed a synthesis pathway for a novel water-soluble TLR2-active analogue, Pam2CS-DMAPA (13), which enhanced the immunogenicity of recombinant SARS-CoV2 and hepatitis B antigens in mice. Co-formulation of compound 13 with 2 % aluminium hydroxide gel led to a further significant improvement in vaccine immunogenicity. This synthetically simpler compound 13 was water soluble and equally potent to Pam2CSK4 adjuvant, but was superior in terms of manufacturing simplicity and scalability. This makes compound 13 a promising TLR2 targeted adjuvant for further development.
期刊介绍:
Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry.
For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature.
The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.