Summary
A bioRxiv preprint reports that NOSTRA, a small molecule found through a DNA-encoded library screen, stabilises the NOS1AP–SCRIB interaction. In Alzheimer’s patient-derived neurons, the researchers report changes in several cellular measures, including amyloid-beta ratio, p-tau217 and network activity.
Researchers report that a small molecule called NOSTRA stabilised the interaction between two proteins, NOS1AP and SCRIB, in experiments that included neurons derived from people with Alzheimer’s disease. The findings are described in a bioRxiv preprint, so they should be read as early-stage laboratory research.
The work takes a different approach to NOS1AP, a protein that acts as an adaptor for neuronal nitric oxide synthase and interacts with several partner proteins. Rather than trying to disrupt one of those interactions, the researchers used a molecule to strengthen a specific one: the connection between NOS1AP and SCRIB.
How the researchers found NOSTRA
The team screened a DNA-encoded library containing 1.4 billion members and identified a benzimidazole-5-carboxamide chemical starting point. They then used fragment-directed structure–activity relationship optimisation—a process of changing parts of a molecule and assessing how those changes affect its properties—to develop NOSTRA. The preprint reports submicromolar binding affinity for NOS1AP.
Across six NOS1AP interactions tested, NOSTRA enhanced binding only to SCRIB. The authors report a cooperativity factor of 30, with the effect arising predominantly from a 14-fold slowing of the complex’s dissociation. Native mass spectrometry detected a three-part complex containing NOS1AP, NOSTRA and SCRIB. In this context, a “molecular glue” is a compound that promotes or stabilises an interaction between proteins.
Effects in cultured neurons
In healthy human induced pluripotent stem cell-derived cortical neurons, NOSTRA engaged the naturally present NOS1AP–SCRIB complex and activated Rac1, a signalling protein. The authors report no cytotoxicity in these experiments.
In Alzheimer’s patient-derived neurons, treatment with NOSTRA lowered the amyloid-beta 42-to-40 ratio and p-tau217, reduced neurofilament light, and improved measured network activity. These are cellular findings, not evidence that NOSTRA treats Alzheimer’s disease in people. The researchers also report an in vitro absorption, distribution, metabolism and excretion profile they consider consistent with possible central nervous system exposure; that profile is not a measurement of drug levels in the brain.
The results identify stabilising a NOS1AP interaction as a possible drug-discovery strategy and provide a candidate molecule for further study. The evidence remains at the cultured-cell stage, and the report is a preprint rather than a peer-reviewed publication.