A novel and potent brain penetrant inhibitor of extracellular vesicle release.

ABSTRACT:

Background and purpose

Extracellular vesicles (EVs) are constitutively shed from cells and released by various stimuli. Their protein and RNA cargo are modified by the stimulus, and in disease conditions can carry pathological cargo involved in disease progression. Neutral sphingomyelinase 2 (nSMase2) is a major regulator in at least one of several independent routes of EV biogenesis, and its inhibition is a promising new therapeutic approach for neurological disorders. Unfortunately, known inhibitors exhibit μM potency, poor physicochemical properties, and/or limited brain penetration. Here, we sought to identify a drug-like inhibitor of nSMase2.

Experimental approach

We conducted a human nSMase2 high throughput screen (>365,000 compounds). Selected hits were optimized focu

SUBMITTER: Rojas C 

PROVIDER: S-EPMC6780992 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature