DNA-Encoded Library-Guided Discovery of a First-in-Class Molecular Glue of the NOS1AP-SCRIB Complex in Alzheimer's Disease Patient-Derived Neurons
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…
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.
Traditionally, 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.
NOSTRA, 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.
To 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.
Even 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.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
