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Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide

The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a...

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Autores principales: Bak, Mijeong, Park, Junyong, Min, Kiyoon, Cho, Jinhwan, Seong, Jihyoun, Hahn, Young S., Tae, Giyoong, Kwon, Inchan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238188/
https://www.ncbi.nlm.nih.gov/pubmed/32316169
http://dx.doi.org/10.3390/pharmaceutics12040364
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author Bak, Mijeong
Park, Junyong
Min, Kiyoon
Cho, Jinhwan
Seong, Jihyoun
Hahn, Young S.
Tae, Giyoong
Kwon, Inchan
author_facet Bak, Mijeong
Park, Junyong
Min, Kiyoon
Cho, Jinhwan
Seong, Jihyoun
Hahn, Young S.
Tae, Giyoong
Kwon, Inchan
author_sort Bak, Mijeong
collection PubMed
description The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A “clickable” non-natural amino acid—p-azido-l-phenylalanine (AzF)—was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide–alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives.
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spelling pubmed-72381882020-05-28 Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide Bak, Mijeong Park, Junyong Min, Kiyoon Cho, Jinhwan Seong, Jihyoun Hahn, Young S. Tae, Giyoong Kwon, Inchan Pharmaceutics Article The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A “clickable” non-natural amino acid—p-azido-l-phenylalanine (AzF)—was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide–alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives. MDPI 2020-04-16 /pmc/articles/PMC7238188/ /pubmed/32316169 http://dx.doi.org/10.3390/pharmaceutics12040364 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bak, Mijeong
Park, Junyong
Min, Kiyoon
Cho, Jinhwan
Seong, Jihyoun
Hahn, Young S.
Tae, Giyoong
Kwon, Inchan
Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide
title Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide
title_full Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide
title_fullStr Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide
title_full_unstemmed Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide
title_short Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide
title_sort recombinant peptide production platform coupled with site-specific albumin conjugation enables a convenient production of long-acting therapeutic peptide
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238188/
https://www.ncbi.nlm.nih.gov/pubmed/32316169
http://dx.doi.org/10.3390/pharmaceutics12040364
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