Department of Chemistry Seminar – Dr. Rana Rais, Johns Hopkins University

About the event

Speaker: Dr. Rana Rais, Johns Hopkins University

Host: Dr. Anjali Sharma

Title: Enhancing Pharmacokinetics of nSMase2 Inhibitors via Prodrugs and Dendrimer Nanoparticle Delivery Systems

Abstract:

Extracellular vesicles (EVs) carry pathological cargo and contribute to disease progression. Membrane ceramide enrichment, regulated by the enzyme neutral Sphingomyelinase-2 (nSMase2), is critical for EV biogenesis, making nSMase2 a promising therapeutic target. Our group identified 2,6-Dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)phenol (DPTIP) as the most potent and selective nSMase2 inhibitor (IC50=30 nM) to date. However, DPTIP’s poor oral pharmacokinetics (PK), limited brain penetration, and rapid clearance restrict its clinical potential. To overcome these limitations and improve DPTIP’s PK, we explored drug delivery strategies. First, a series of prodrugs were synthesized, with the best candidate showing over fourfold higher plasma and brain exposure and an extended half-life in mice. Second, DPTIP was conjugated to a hydroxyl-PAMAM dendrimer (D-DPTIP), which, when orally administered, significantly inhibited IL-1β-induced EV release and blocked pTau propagation in mouse models of brain injury. Both the prodrug and dendrimer-DPTIP delivery systems demonstrated enhanced PK properties and therapeutic efficacy, underscoring their potential for clinical translation in EV-related pathologies, including Alzheimer’s disease.