Engineering isoform-selective miniprotein binders to the fetal form of the insulin receptor

Clicks: 39
ID: 326972
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Emerging

Ranked #18 of 38 articles by views in Protein Engineering Design and Selection

Most read Least read

Bar heights use a square-root scale.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
Abstract The fetal form of the insulin receptor (IRA) is predominantly expressed in many cancers, where IR signaling promotes progression of the disease. Alternatively, the adult IR isoform (IRB) is predominantly expressed in normal tissues. Previous attempts to target IR indiscriminately via dual IR/IGF1R tyrosine kinase inhibitors frequently failed due to on-target off-tumor effects. However, an IRA-specific therapeutic has the potential to specifically target cancer while sparing normal tissues. Furthermore, an IRA-specific binder would advance research regarding this disease-associated isoform. Yet, isoform-specific IR binders have not been developed. Herein, we engineer six high-affinity, IRA-specific protein binders from a synthetic miniprotein scaffold. These miniprotein variants have IRA KDs ranging from 0.98–7.6 nM with no appreciable IRB binding at 100 nM ligand. Five of the six variants are synergistic agonists. One variant (V1) is a passive, IRA-specific binder with a KD = 6.3 nM and no IRB binding at 1 μM ligand as well as no IGF1R binding at 100 nM, which provides compelling potential as a targeted therapeutic. Additionally, we present the discovery process for these molecules, a yeast display directed evolution campaign utilizing a combination of sorting techniques. Retrospective analysis of the discovery process revealed the importance of alternating selections for target affinity and isoform specificity to generate binders with a favorable combination of these properties.
Reference Key
openalex_W7206204505 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Melissa A Walsh, Paul L. Blanchard, Xihong Zhang, Nathaniel T Cheung, Douglas Yee, Benjamin J. Hackel
Are you one of these authors? Claim your profile
Journal Protein Engineering Design and Selection
Year 2026
DOI
10.1093/protein/gzag025
URL
https://doi.org/10.1093/protein/gzag025
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.