Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA-Displayed Peptide Libraries

Paddy R.A. Melsen; Ryoji Yoshisada; Seino A.K. Jongkees

doi:10.1002/cbic.202100685

Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA-Displayed Peptide Libraries

Paddy R.A. Melsen, Ryoji Yoshisada, Seino A.K. Jongkees^*

^*Corresponding author for this work

Research output: Contribution to Journal › Review article › Academic › peer-review

Abstract

DNA-encoded small-molecule libraries and mRNA displayed peptide libraries both use numerically large pools of oligonucleotide-tagged molecules to identify potential hits for protein targets. They differ dramatically, however, in the ‘drug-likeness’ of the molecules that each can be used to discover. We give here an overview of the two techniques, comparing some advantages and disadvantages of each, and suggest areas where particularly mRNA display can benefit from adopting advances developed with DNA-encoded small molecule libraries. We outline cases where chemical modification of the peptide library has already been used in mRNA display, and survey opportunities to expand this using examples from DNA-encoded small molecule libraries. We also propose potential opportunities for encoding such reactions within the mRNA/cDNA tag of an mRNA-displayed peptide library to allow a more diversity-oriented approach to library modification. Finally, we outline alternate approaches for enriching target-binding hits from a pooled and tagged library, and close by detailing several examples of how an adjusted mRNA-display based approach could be used to discover new ‘drug-like’ modified small peptides.

Original language	English
Article number	e202100685
Pages (from-to)	1-19
Number of pages	19
Journal	ChemBioChem
Volume	23
Issue number	12
Early online date	31 Jan 2022
DOIs	https://doi.org/10.1002/cbic.202100685
Publication status	Published - 20 Jun 2022

Bibliographical note

Funding Information:
. Seino Jongkees is Assistant Professor in the department of Chemistry and Pharmaceutical Sciences at the Amsterdam Institute of Molecular and Life Sciences, VU Amsterdam. He received his B.Sc. and BA from Otago University (New Zealand), then pursued a Ph.D. at the University of British Columbia working with Prof. Withers. Subsequently, he took a JSPS postdoctoral fellowship at the University of Tokyo with Prof. Suga. In 2016 he moved to Utrecht University to establish his own research group before being recruited to VU Amsterdam at the beginning of 2021. Research in the group is focused on the discovery of peptide ligands for carbohydrate‐active enzymes and carbohydrate‐binding proteins as inhibitors and probes, as well as exploring new reactions for diversification in mRNA display

Funding Information:
S. A. K. J. and R. Y. acknowledge financial support from NWO-klein2 grant number OCENW.KLEIN.248 of the Dutch Research Council. R. Y. additionally acknowledges support of the Takenaka Scholarship Foundation. Figures created with BioRender.com.

Funding Information:
S. A. K. J. and R. Y. acknowledge financial support from NWO‐klein2 grant number OCENW.KLEIN.248 of the Dutch Research Council. R. Y. additionally acknowledges support of the Takenaka Scholarship Foundation. Figures created with BioRender.com.

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

Funding

. Seino Jongkees is Assistant Professor in the department of Chemistry and Pharmaceutical Sciences at the Amsterdam Institute of Molecular and Life Sciences, VU Amsterdam. He received his B.Sc. and BA from Otago University (New Zealand), then pursued a Ph.D. at the University of British Columbia working with Prof. Withers. Subsequently, he took a JSPS postdoctoral fellowship at the University of Tokyo with Prof. Suga. In 2016 he moved to Utrecht University to establish his own research group before being recruited to VU Amsterdam at the beginning of 2021. Research in the group is focused on the discovery of peptide ligands for carbohydrate‐active enzymes and carbohydrate‐binding proteins as inhibitors and probes, as well as exploring new reactions for diversification in mRNA display S. A. K. J. and R. Y. acknowledge financial support from NWO-klein2 grant number OCENW.KLEIN.248 of the Dutch Research Council. R. Y. additionally acknowledges support of the Takenaka Scholarship Foundation. Figures created with BioRender.com. S. A. K. J. and R. Y. acknowledge financial support from NWO‐klein2 grant number OCENW.KLEIN.248 of the Dutch Research Council. R. Y. additionally acknowledges support of the Takenaka Scholarship Foundation. Figures created with BioRender.com.

Keywords

bioorthogonal chemistry
DNA-encoded libraries
drug discovery
mRNA display
peptide drugs

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title = "Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA-Displayed Peptide Libraries",

abstract = "DNA-encoded small-molecule libraries and mRNA displayed peptide libraries both use numerically large pools of oligonucleotide-tagged molecules to identify potential hits for protein targets. They differ dramatically, however, in the {\textquoteleft}drug-likeness{\textquoteright} of the molecules that each can be used to discover. We give here an overview of the two techniques, comparing some advantages and disadvantages of each, and suggest areas where particularly mRNA display can benefit from adopting advances developed with DNA-encoded small molecule libraries. We outline cases where chemical modification of the peptide library has already been used in mRNA display, and survey opportunities to expand this using examples from DNA-encoded small molecule libraries. We also propose potential opportunities for encoding such reactions within the mRNA/cDNA tag of an mRNA-displayed peptide library to allow a more diversity-oriented approach to library modification. Finally, we outline alternate approaches for enriching target-binding hits from a pooled and tagged library, and close by detailing several examples of how an adjusted mRNA-display based approach could be used to discover new {\textquoteleft}drug-like{\textquoteright} modified small peptides.",

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author = "Melsen, {Paddy R.A.} and Ryoji Yoshisada and Jongkees, {Seino A.K.}",

note = "Funding Information: . Seino Jongkees is Assistant Professor in the department of Chemistry and Pharmaceutical Sciences at the Amsterdam Institute of Molecular and Life Sciences, VU Amsterdam. He received his B.Sc. and BA from Otago University (New Zealand), then pursued a Ph.D. at the University of British Columbia working with Prof. Withers. Subsequently, he took a JSPS postdoctoral fellowship at the University of Tokyo with Prof. Suga. In 2016 he moved to Utrecht University to establish his own research group before being recruited to VU Amsterdam at the beginning of 2021. Research in the group is focused on the discovery of peptide ligands for carbohydrate‐active enzymes and carbohydrate‐binding proteins as inhibitors and probes, as well as exploring new reactions for diversification in mRNA display Funding Information: S. A. K. J. and R. Y. acknowledge financial support from NWO-klein2 grant number OCENW.KLEIN.248 of the Dutch Research Council. R. Y. additionally acknowledges support of the Takenaka Scholarship Foundation. Figures created with BioRender.com. Funding Information: S. A. K. J. and R. Y. acknowledge financial support from NWO‐klein2 grant number OCENW.KLEIN.248 of the Dutch Research Council. R. Y. additionally acknowledges support of the Takenaka Scholarship Foundation. Figures created with BioRender.com. Publisher Copyright: {\textcopyright} 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.",

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N2 - DNA-encoded small-molecule libraries and mRNA displayed peptide libraries both use numerically large pools of oligonucleotide-tagged molecules to identify potential hits for protein targets. They differ dramatically, however, in the ‘drug-likeness’ of the molecules that each can be used to discover. We give here an overview of the two techniques, comparing some advantages and disadvantages of each, and suggest areas where particularly mRNA display can benefit from adopting advances developed with DNA-encoded small molecule libraries. We outline cases where chemical modification of the peptide library has already been used in mRNA display, and survey opportunities to expand this using examples from DNA-encoded small molecule libraries. We also propose potential opportunities for encoding such reactions within the mRNA/cDNA tag of an mRNA-displayed peptide library to allow a more diversity-oriented approach to library modification. Finally, we outline alternate approaches for enriching target-binding hits from a pooled and tagged library, and close by detailing several examples of how an adjusted mRNA-display based approach could be used to discover new ‘drug-like’ modified small peptides.

AB - DNA-encoded small-molecule libraries and mRNA displayed peptide libraries both use numerically large pools of oligonucleotide-tagged molecules to identify potential hits for protein targets. They differ dramatically, however, in the ‘drug-likeness’ of the molecules that each can be used to discover. We give here an overview of the two techniques, comparing some advantages and disadvantages of each, and suggest areas where particularly mRNA display can benefit from adopting advances developed with DNA-encoded small molecule libraries. We outline cases where chemical modification of the peptide library has already been used in mRNA display, and survey opportunities to expand this using examples from DNA-encoded small molecule libraries. We also propose potential opportunities for encoding such reactions within the mRNA/cDNA tag of an mRNA-displayed peptide library to allow a more diversity-oriented approach to library modification. Finally, we outline alternate approaches for enriching target-binding hits from a pooled and tagged library, and close by detailing several examples of how an adjusted mRNA-display based approach could be used to discover new ‘drug-like’ modified small peptides.

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KW - peptide drugs

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Opportunities for Expanding Encoded Chemical Diversification and Improving Hit Enrichment in mRNA-Displayed Peptide Libraries

Abstract

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Keywords

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