Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency

Jacob T Martin,1 Marc Douaisi,2 Ammar Arsiwala,3 Manish Arha,2 Ravi S Kane3 1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; 2Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA; 3School o...

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Autores principales:	Martin JT, Douaisi M, Arsiwala A, Arha M, Kane RS
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	Polyvalency grafting oligonucleotide polyglutamic acid Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/2933321aad9541608df24aee474d081b
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spelling	oai:doaj.org-article:2933321aad9541608df24aee474d081b2021-12-02T03:17:52ZSynthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency1178-2013https://doaj.org/article/2933321aad9541608df24aee474d081b2018-09-01T00:00:00Zhttps://www.dovepress.com/synthesis-of-multivalent-polymer-aptamer-conjugates-with-enhanced-inhi-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Jacob T Martin,1 Marc Douaisi,2 Ammar Arsiwala,3 Manish Arha,2 Ravi S Kane3 1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; 2Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA; 3School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA Purpose: We are interested in designing a modular strategy for creating potent multivalent ligands, which frequently can be used as effective inhibitors of undesired biomolecular interactions. For example, such inhibitors might prevent the self-assembly of bacterial toxins or the attachment of a virus to its host cell receptors. Methods: We used a biocompatible polyamino acid polymer as a scaffold for grafting multiple copies of an oligonucleotide aptamer (OA). Specifically, the carboxylates on the side chains of polyglutamic acid (PGA) were modified with a thiol-reactive linker, N-aminoethyl maleimide (AEM), and thiol-functionalized OAs were attached to the maleimide moieties. The resulting conjugates were tested for their ability to compete with and inhibit the binding of unconjugated monovalent OAs to the target cell receptor. Results: Multivalent PGA–OA conjugates with low, medium, and high valency were successfully prepared. The varying valency and successful purification to remove unconjugated OAs were confirmed by polyacrylamide gel electrophoresis. The resulting purified conjugates inhibited the binding of unconjugated monovalent OAs, and the measured half maximal inhibitory concentration (IC50) values corresponded to a 38–88-fold enhancement of potency on a per-aptamer basis, relative to OA alone. Conclusion: Multivalent conjugation of OA ligands has potential as a generally useful way to improve the potency of the interaction between the ligand and its target receptor. We have demonstrated this principle with a known OA as a proof of concept as well a synthetic strategy that can be used to synthesize multivalent conjugates of other OAs. Keywords: polyvalency, grafting, oligonucleotide, polyglutamic acidMartin JTDouaisi MArsiwala AArha MKane RSDove Medical PressarticlePolyvalencygraftingoligonucleotidepolyglutamic acidMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 5249-5253 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Polyvalency grafting oligonucleotide polyglutamic acid Medicine (General) R5-920
spellingShingle	Polyvalency grafting oligonucleotide polyglutamic acid Medicine (General) R5-920 Martin JT Douaisi M Arsiwala A Arha M Kane RS Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency
description	Jacob T Martin,1 Marc Douaisi,2 Ammar Arsiwala,3 Manish Arha,2 Ravi S Kane3 1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; 2Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA; 3School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA Purpose: We are interested in designing a modular strategy for creating potent multivalent ligands, which frequently can be used as effective inhibitors of undesired biomolecular interactions. For example, such inhibitors might prevent the self-assembly of bacterial toxins or the attachment of a virus to its host cell receptors. Methods: We used a biocompatible polyamino acid polymer as a scaffold for grafting multiple copies of an oligonucleotide aptamer (OA). Specifically, the carboxylates on the side chains of polyglutamic acid (PGA) were modified with a thiol-reactive linker, N-aminoethyl maleimide (AEM), and thiol-functionalized OAs were attached to the maleimide moieties. The resulting conjugates were tested for their ability to compete with and inhibit the binding of unconjugated monovalent OAs to the target cell receptor. Results: Multivalent PGA–OA conjugates with low, medium, and high valency were successfully prepared. The varying valency and successful purification to remove unconjugated OAs were confirmed by polyacrylamide gel electrophoresis. The resulting purified conjugates inhibited the binding of unconjugated monovalent OAs, and the measured half maximal inhibitory concentration (IC50) values corresponded to a 38–88-fold enhancement of potency on a per-aptamer basis, relative to OA alone. Conclusion: Multivalent conjugation of OA ligands has potential as a generally useful way to improve the potency of the interaction between the ligand and its target receptor. We have demonstrated this principle with a known OA as a proof of concept as well a synthetic strategy that can be used to synthesize multivalent conjugates of other OAs. Keywords: polyvalency, grafting, oligonucleotide, polyglutamic acid
format	article
author	Martin JT Douaisi M Arsiwala A Arha M Kane RS
author_facet	Martin JT Douaisi M Arsiwala A Arha M Kane RS
author_sort	Martin JT
title	Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency
title_short	Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency
title_full	Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency
title_fullStr	Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency
title_full_unstemmed	Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency
title_sort	synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/2933321aad9541608df24aee474d081b
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Synthesis of multivalent polymer&ndash;aptamer conjugates with enhanced inhibitory potency

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Synthesis of multivalent polymer–aptamer conjugates with enhanced inhibitory potency