Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation

Yunn, Na-Oh; Koh, Ara; Han, Seungmin; Lim, Jong Hun; Park, Sehoon; Lee, Jiyoun; Kim, Eui; Jang, Sung Key; Berggren, Per Olof; Ryu, Sung Ho

doi:10.1093/nar/gkv767

Cited by 57 publications

(44 citation statements)

References 61 publications

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“…This includes RNA aptamers targeting human epidermal growth factor receptor-3 (HER3/ERBB3) 116 , OX40 (CD134) 117, 118 , 4-1BB (CD137) 119 , CD40 120 , CD28 121 , and DNA aptamers targeting human VEGFR-2 122 and the insulin receptor (IR) 123 . Several of the RNA aptamers targeting immune costimulatory receptors (CD28, CD40, OX40 and 4-1BB) have been engineered into multimeric versions to act as receptor agonists for improved cancer immunotherapy 124 .…”

Section: Recent Progress In Aptamer-based Therapeuticsmentioning

confidence: 99%

Aptamers as targeted therapeutics: current potential and challenges

Zhou

Rossi

2016

Nat Rev Drug Discov

1,459

1,316

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Nucleic acid aptamers, often termed “chemical antibodies”, are functionally comparable to traditional antibodies, but offer several advantages including their relatively small physical size, flexible structure, quick chemical production, versatile chemical modification, high stability, and lack of immunogenicity. In addition, many aptamers internalize upon binding to cellular receptors making them useful targeted delivery agents for siRNAs, microRNAs and conventional drugs. However,Ge several crucial factors, such as their inherent physicochemical characteristics and lack of safety data, have delayed the clinical translation of therapeutic aptamers. This review discusses these challenges, highlighting recent clinical developments and technological advances that have revived impetus for this promising class of therapeutics.

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Section: Recent Progress In Aptamer-based Therapeuticsmentioning

confidence: 99%

Aptamers as targeted therapeutics: current potential and challenges

Zhou

Rossi

2016

Nat Rev Drug Discov

1,459

1,316

View full text Add to dashboard Cite

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“…The activated RTKs can trigger intracellular signal transduction events and transcriptional changes to regulate various cellular functions. Analogous approaches have been reported for the design of agonistic aptamers for the insulin receptor (16) and immune costimulatory receptors (17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application

et al. 2020

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Although growth factors have great therapeutic potential because of their regenerative functions, they often have intrinsic drawbacks, such as low thermal stability and high production cost. Oligonucleotides have recently emerged as promising chemical entities for designing synthetic alternatives to growth factors. However, their applications in vivo have been recognized as a challenge because of their susceptibility to nucleases and limited distribution to a target tissue. Here, we present the first example of oligonucleotide-based growth factor mimetics that exerts therapeutic effects at a target tissue after systemic injection. The aptamer was designed to dimerize a growth factor receptor for its activation and mitigated the progression of Fas-induced fulminant hepatitis in a mouse model. This unprecedented functionality of the aptamer can be reasonably explained by its high nuclease stability and migration to the liver parenchyma. These mechanistic analyses provided insights for the successful application of aptamer-based receptor agonists.

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“…However, these canonical models for IR activation cannot explain how the biased agonists regulate receptor autophosphorylation and intracellular signaling in a distinct manner from insulin. In particular, IR-A48, an aptamer agonist of IR, not only selectively activates the PI3K/AKT pathway and glucose uptake, but also induces mono-phosphorylation of Tyr1150 residue (m-pY1150) in the kinase domain of IR without phosphorylating other tyrosine residues 11 . This led us to hypothesize that m-pY1150 is a key link between the biased intracellular signaling and receptor modulation by biased agonists.…”

Section: Introduction and Resultsmentioning

confidence: 99%

Stepwise autophosphorylation regulates biased agonism of the insulin receptor

Yunn

Park

Noh

et al. 2019

Preprint

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SummaryInsulin is a key regulator of energy metabolism in peripheral tissues but also functions as a growth factor. Insulin binding to the insulin receptor (IR) leads to autophosphorylation of intracellular tyrosine residues, which simultaneously initiates a multitude of signals and functions. In contrast, some artificial (non-insulin) ligands for the IR result in biased agonism, selectively activating the PI3K/AKT pathway and metabolic effects without activating mitogen-activated protein kinase (MAPK) pathway and mitogenic effects. However, the precise mechanism of biased agonism at the receptor level remains unclear. The biased agonist IR-A48 aptamer selectively induces mono-phosphorylation of Tyr1150 residue (m-pY1150) in the kinase domain of IR. Hence, we hypothesized that IR autophosphorylation is a stepwise process in which formation of m-pY1150 represents an intermediate step. To explore this idea, we used hybrid receptors in which insulin can bind only one of the two binding sites of the dimeric receptor. Asymmetric insulin binding selectively induced symmetric m-pY1150 in both kinase domains. Moreover, the juxtamembrane domain, which interacts with the kinase domain, restricted the full activation of IR, and symmetric m-pY1150 played a crucial role in the rearrangement of intracellular domains to release this restriction. Our findings demonstrate that the symmetry of insulin binding to a dimeric receptor determines the stepwise autophosphorylation of IR. Furthermore, considering that the degree of ligand symmetry on a receptor depends mainly on ligand concentration, our results suggest that IR may play metabolic-biased roles in peripheral tissues dependent on local insulin concentrations.

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Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation

Cited by 57 publications

References 61 publications

Aptamers as targeted therapeutics: current potential and challenges

Aptamers as targeted therapeutics: current potential and challenges

A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application

Stepwise autophosphorylation regulates biased agonism of the insulin receptor

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