Conjugation of a Toll-Like Receptor Agonist to Glycans of an HIV Native-Like Envelope Trimer Preserves Neutralization Epitopes

Zeshi Li; Ronald Derking; Wen-Hsin Lee; Gerlof P Bosman; Andrew B Ward; Rogier W Sanders; Geert-Jan Boons

doi:10.1002/cbic.202200236

Conjugation of a Toll-Like Receptor Agonist to Glycans of an HIV Native-Like Envelope Trimer Preserves Neutralization Epitopes

Zeshi Li
, Ronald Derking
, Wen-Hsin Lee
, Gerlof P Bosman
, Andrew B Ward
, Rogier W Sanders
, Geert-Jan Boons

University of Amsterdam
Scripps Research Institute

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Small molecule adjuvants are attractive for enhancing broad protection and durability of immune responses elicited by subunit vaccines. Covalent attachment of an adjuvant to an immunogen is particularly attractive because it simultaneously delivers both entities to antigen presenting cells resulting in more efficient immune activation. There is, however, a lack of methods to conjugate small molecule immune potentiators to viral glycoprotein immunogens without compromising epitope integrity. We describe herein a one-step enzymatic conjugation approach for the covalent attachment of small molecule adjuvants to N-linked glycans of viral glycoproteins. It involves the attachment of an immune potentiator to CMP-Neu5AcN 3 by Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition followed by sialyltransferase-mediated transfer to N-glycans of a viral glycoprotein. The method was employed to modify a native-like HIV envelope trimer with a Toll-like receptor 7/8 agonist. The modification did not compromise Env-trimer recognition by several broadly neutralization antibodies. Electron microscopy confirmed structural integrity of the modified immunogen.

Original language	English
Article number	e202200236
Pages (from-to)	1-7
Journal	ChemBioChem
Volume	23
Issue number	16
Early online date	1 Jun 2022
DOIs	https://doi.org/10.1002/cbic.202200236
Publication status	Published - 17 Aug 2022

Bibliographical note

Funding Information:
The research was supported by TOP‐PUNT grant 718.015.003 of the Netherlands Organization for Scientific Research (G.J.B.), the National Institutes of Health (NIH) under grant P0 AI110657 (R.W.S. and A.B.W.); the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery under grant INV‐002022 (R.W.S.) and OPP1115782/INV‐002916 (A.B.W.); the European Union Horizon 2020 research and innovation program under grant 681137 (R.W.S.).

Funding Information:
The research was supported by TOP-PUNT grant 718.015.003 of the Netherlands Organization for Scientific Research (G.J.B.), the National Institutes of Health (NIH) under grant P0 AI110657 (R.W.S. and A.B.W.); the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery under grant INV-002022 (R.W.S.) and OPP1115782/INV-002916 (A.B.W.); the European Union Horizon 2020 research and innovation program under grant 681137 (R.W.S.).

Publisher Copyright:
© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Toll-like receptor agonist
carbohydrates
conjugation
glycosyl transferases
vaccines

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10.1002/cbic.202200236Licence: CC BY

ChemBioChem - 2022 - Li - Conjugation of a Toll‐Like Receptor Agonist to Glycans of an HIV Native‐Like Envelope TrimerFinal published version, 1.1 MBLicence: CC BY

Cite this

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title = "Conjugation of a Toll-Like Receptor Agonist to Glycans of an HIV Native-Like Envelope Trimer Preserves Neutralization Epitopes",

abstract = "Small molecule adjuvants are attractive for enhancing broad protection and durability of immune responses elicited by subunit vaccines. Covalent attachment of an adjuvant to an immunogen is particularly attractive because it simultaneously delivers both entities to antigen presenting cells resulting in more efficient immune activation. There is, however, a lack of methods to conjugate small molecule immune potentiators to viral glycoprotein immunogens without compromising epitope integrity. We describe herein a one-step enzymatic conjugation approach for the covalent attachment of small molecule adjuvants to N-linked glycans of viral glycoproteins. It involves the attachment of an immune potentiator to CMP-Neu5AcN 3 by Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition followed by sialyltransferase-mediated transfer to N-glycans of a viral glycoprotein. The method was employed to modify a native-like HIV envelope trimer with a Toll-like receptor 7/8 agonist. The modification did not compromise Env-trimer recognition by several broadly neutralization antibodies. Electron microscopy confirmed structural integrity of the modified immunogen. ",

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note = "Funding Information: The research was supported by TOP‐PUNT grant 718.015.003 of the Netherlands Organization for Scientific Research (G.J.B.), the National Institutes of Health (NIH) under grant P0 AI110657 (R.W.S. and A.B.W.); the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery under grant INV‐002022 (R.W.S.) and OPP1115782/INV‐002916 (A.B.W.); the European Union Horizon 2020 research and innovation program under grant 681137 (R.W.S.). Funding Information: The research was supported by TOP-PUNT grant 718.015.003 of the Netherlands Organization for Scientific Research (G.J.B.), the National Institutes of Health (NIH) under grant P0 AI110657 (R.W.S. and A.B.W.); the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery under grant INV-002022 (R.W.S.) and OPP1115782/INV-002916 (A.B.W.); the European Union Horizon 2020 research and innovation program under grant 681137 (R.W.S.). Publisher Copyright: {\textcopyright} 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.",

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AU - Bosman, Gerlof P

AU - Ward, Andrew B

AU - Sanders, Rogier W

AU - Boons, Geert-Jan

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N2 - Small molecule adjuvants are attractive for enhancing broad protection and durability of immune responses elicited by subunit vaccines. Covalent attachment of an adjuvant to an immunogen is particularly attractive because it simultaneously delivers both entities to antigen presenting cells resulting in more efficient immune activation. There is, however, a lack of methods to conjugate small molecule immune potentiators to viral glycoprotein immunogens without compromising epitope integrity. We describe herein a one-step enzymatic conjugation approach for the covalent attachment of small molecule adjuvants to N-linked glycans of viral glycoproteins. It involves the attachment of an immune potentiator to CMP-Neu5AcN 3 by Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition followed by sialyltransferase-mediated transfer to N-glycans of a viral glycoprotein. The method was employed to modify a native-like HIV envelope trimer with a Toll-like receptor 7/8 agonist. The modification did not compromise Env-trimer recognition by several broadly neutralization antibodies. Electron microscopy confirmed structural integrity of the modified immunogen.

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Conjugation of a Toll-Like Receptor Agonist to Glycans of an HIV Native-Like Envelope Trimer Preserves Neutralization Epitopes

Abstract

Bibliographical note

UN SDGs

Keywords

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