{
  "id": 15433677,
  "title": "DNA-Encoded Library-Guided Discovery of a First-in-Class Molecular Glue of the NOS1AP-SCRIB Complex in Alzheimer's Disease Patient-Derived Neurons",
  "url": "https://urgent.news/2026/10/18/dna-encoded-library-guided-discovery-of-a-first-in-class-molecular",
  "topic": "health",
  "section": "Health & Medicine",
  "published": "2026-10-18T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758423v1?rss=1"
  },
  "original_language": "en",
  "account": "A groundbreaking discovery in the realm of Alzheimer's disease research has emerged from the innovative use of a DNA-encoded library for drug discovery. The focus of this study revolves around the NOS1AP-SCRIB complex, an interaction implicated in Alzheimer's progression.\n\nTraditionally, efforts to develop drugs targeting NOS1AP have aimed to disrupt its interactions. However, the research team took a different approach, seeking to pharmacologically stabilize one specific interaction. To accomplish this, they screened a library containing 1.4 billion members, ultimately identifying a compound named NOSTRA.\n\nNOSTRA, a benzimidazole-5-carboxamide chemotype, was selected based on its submicromolar binding affinity to NOS1AP. It exhibited remarkable selectivity, enhancing only the SCRIB binding within a set of six interactions, with a high cooperativity factor of 30. This enhancement was primarily due to a 14-fold reduction in the dissociation rate of the NOS1AP-SCRIB complex.\n\nTo validate their findings, the researchers utilized native mass spectrometry, which confirmed the formation of a NOS1AP:NOSTRA:SCRIB ternary complex. Excitingly, in healthy human iPSC-derived cortical neurons, NOSTRA effectively engaged the endogenous NOS1AP-SCRIB complex and activated Rac1, all without causing cytotoxicity.\n\nEven more promising, in Alzheimer's patient-derived neurons, NOSTRA demonstrated significant therapeutic potential. It lowered the Aβ42/Aβ40 ratio and p-tau217, reduced neurofilament light, and improved network activity. Furthermore, NOSTRA's in vitro ADME profile indicated a favorable profile for CNS exposure, making it a promising candidate for future Alzheimer's disease therapies. This breakthrough marks the first instance of a molecular glue for the NOS1AP complex, establishing interaction stabilization as a viable strategy in NOS1AP pharmacology.",
  "summary": "NOS1AP is an adaptor for neuronal nitric oxide synthase that engages several partner proteins and is implicated in Alzheimer's disease. Efforts to drug NOS1AP have sought to disrupt these; we instead report pharmacological stabilization of one interaction. Affinity selection of a 1.4-billion-member DNA-encoded library identified a benzimidazole-5-carboxamide chemotype, optimized by…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}