Structural Superimposition

Abstact

The investigational drug zervimesine (CT1812) is an allosteric small molecule modulator of the sigma-2 receptor (S2R), known as transmembrane protein 97 (TMEM97), currently in clinical development for Alzheimer's disease and dementia with Lewy bodies. In Phase 2 trials, consistent favorable trends across outcome measures were observed for Alzheimer's disease (NCT03507790), dementia with Lewy Bodies (NCT05225415), and another indication, dry AMD (NCT05893537). The crystal structure of S2R complexed with zervimesine to 2.74 A resolution reveals this investigational therapeutic bound in the binding site of S2R analogous to that seen previously with other S2R ligands, and is consistent with binding affinity data from a S2R competition assay. The structural interactions by which zervimesine binds with S2R are illuminated, which may shed light on the potential structure-function relationship underlying the favorable effects of zervimesine seen preclinically and clinically, and may foster the design of future S2R modulators for neurodegenerative conditions.