Nipping disease in the bud: nSMase2 inhibitors as therapeutics in extracellular vesicle-mediated diseases

Carolyn Tallon; Kristen R Hollinger; Arindom Pal; Benjamin J Bell; Rana Rais; Takashi Tsukamoto; Kenneth W Witwer; Norman J Haughey; Barbara S Slusher

doi:10.1016/j.drudis.2021.03.025

Nipping disease in the bud: nSMase2 inhibitors as therapeutics in extracellular vesicle-mediated diseases

Drug Discov Today. 2021 Jul;26(7):1656-1668. doi: 10.1016/j.drudis.2021.03.025. Epub 2021 Mar 31.

Authors

Carolyn Tallon¹, Kristen R Hollinger², Arindom Pal¹, Benjamin J Bell¹, Rana Rais¹, Takashi Tsukamoto¹, Kenneth W Witwer³, Norman J Haughey⁴, Barbara S Slusher⁵

Affiliations

¹ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: bslusher@jhmi.edu.

Abstract

Extracellular vesicles (EVs) are indispensable mediators of intercellular communication, but they can also assume a nefarious role by ferrying pathological cargo that contributes to neurological, oncological, inflammatory, and infectious diseases. The canonical pathway for generating EVs involves the endosomal sorting complexes required for transport (ESCRT) machinery, but an alternative pathway is induced by the enrichment of lipid membrane ceramides generated by neutral sphingomyelinase 2 (nSMase2). Inhibition of nSMase2 has become an attractive therapeutic strategy for inhibiting EV biogenesis, and a growing number of small-molecule nSMase2 inhibitors have shown promising therapeutic activity in preclinical disease models. This review outlines the function of EVs, their potential role in disease, the discovery and efficacy of nSMase2 inhibitors, and the path to translate these findings into therapeutics.

Keywords: Biomarker; Cell communication; Ceramide; Drug discovery; Extracellular vesicle; Sphingomyelinase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Drug Resistance
Extracellular Vesicles*
Humans
Immunotherapy
Neoplasms / drug therapy
Neurodegenerative Diseases / drug therapy
Sphingomyelin Phosphodiesterase / antagonists & inhibitors*
Sphingomyelin Phosphodiesterase / metabolism

Substances

SMPD3 protein, human
Sphingomyelin Phosphodiesterase

Abstract

Publication types

MeSH terms

Substances

Grants and funding