Computational De Novo Design of Miniprotein Candidate Neutralizers Targeting the IL-23 Cytokine Subunit p19
Abstract
Interleukin-23 (IL-23) drives T-helper-17 inflammation underlying inflammatory bowel disease and psoriasis; anti-p19 antibodies are clinically effective but large, costly, and injectable. De novo miniproteins are an attractive alternative, yet published designs target the IL-23 receptor; the IL-23 cytokine itself has not been addressed. A further obstacle is that the standard confidence score (ipTM) tracks construct length rather than interface quality. We computationally design miniprotein binders against the IL-23R-binding face of p19 (PDB 3DUH) and score every design with ipSAE, a length-robust interface metric derived from AlphaFold-initial-guess predicted aligned error. A conventional RFdiffusion/ProteinMPNN/ColabFold pipeline yields no reliable predicted interface across 972 designs (best ipSAE 0.30), and a scoring artifact, in which single-sequence ColabFold under-rates binder pLDDT by approximately 56 points, explains an earlier misleading "binders do not fold" signal. An interface-optimized hallucination method (BindCraft), scored identically, yields 42 of 50 designs above ipSAE 0.60 (best 0.804). An AlphaFold-independent geometric check reproduces the conventional failure: no top-ranked conventional design reaches the buried area or interface hydrogen-bond count of the weakest lead. Five all-alpha-helical leads (72-104 residues) collectively engage all six targeted hotspots; two dock within the intact p40/p19 heterodimer and all show favorable Rosetta energetics. A p40-alone counter-screen returns ipSAE 0.00 for all five, indicating no spurious p40 interface. To our knowledge, these are the first computationally proposed de novo miniprotein candidates designed to occlude the IL-23R-binding face of IL-23 p19. All results require experimental validation.
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BibTeX
@misc{paladugu2026computational,
title = {{Computational De Novo Design of Miniprotein Candidate Neutralizers Targeting the IL-23 Cytokine Subunit p19}},
author = {Raghav Paladugu and Fardina Fathmiul Alam},
howpublished = {arXiv},
year = {2026},
month = oct,
doi = {10.48550/arxiv.2610.32779},
eprint = {2610.32779},
archivePrefix = {arXiv},
url = {https://arxiv.org/abs/2610.32779},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Computational De Novo Design of Miniprotein Candidate Neutralizers Targeting the IL-23 Cytokine Subunit p19
AU - Raghav Paladugu
AU - Fardina Fathmiul Alam
PY - 2026
DA - 2026/10/23
PB - arXiv
DO - 10.48550/arxiv.2610.32779
UR - https://arxiv.org/abs/2610.32779
AB - Interleukin-23 (IL-23) drives T-helper-17 inflammation underlying inflammatory bowel disease and psoriasis; anti-p19 antibodies are clinically effective but large, costly, and injectable. De novo miniproteins are an attractive alternative, yet published designs target the IL-23 receptor; the IL-23 cytokine itself has not been addressed. A further obstacle is that the standard confidence score (ipTM) tracks construct length rather than interface quality. We computationally design miniprotein binders against the IL-23R-binding face of p19 (PDB 3DUH) and score every design with ipSAE, a length-robust interface metric derived from AlphaFold-initial-guess predicted aligned error. A conventional RFdiffusion/ProteinMPNN/ColabFold pipeline yields no reliable predicted interface across 972 designs (best ipSAE 0.30), and a scoring artifact, in which single-sequence ColabFold under-rates binder pLDDT by approximately 56 points, explains an earlier misleading "binders do not fold" signal. An interface-optimized hallucination method (BindCraft), scored identically, yields 42 of 50 designs above ipSAE 0.60 (best 0.804). An AlphaFold-independent geometric check reproduces the conventional failure: no top-ranked conventional design reaches the buried area or interface hydrogen-bond count of the weakest lead. Five all-alpha-helical leads (72-104 residues) collectively engage all six targeted hotspots; two dock within the intact p40/p19 heterodimer and all show favorable Rosetta energetics. A p40-alone counter-screen returns ipSAE 0.00 for all five, indicating no spurious p40 interface. To our knowledge, these are the first computationally proposed de novo miniprotein candidates designed to occlude the IL-23R-binding face of IL-23 p19. All results require experimental validation.
ER -