(Current Challenges and Updates in Pharmacy Education and Research)

Design, synthesis and, biological evaluation of PF-543 analogs as a Two Pore Channel Blockers

Not scheduled

20m

كلية الصيدلة

Live presentation Conference Track Three

Speaker

ALI HAMZAH (PhD candidate, university of Toledo, department of medicinal and biological chemistry)

Description

ABSTRACT
Two-pore channels (TPCs) are Ca2+-permeable endolysosomal ion channels responsible for calcium release from acidic stores in response to the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Recently, TPCs have emerged as a promising drug target. Although the pharmacology of TPCs a still in its infancy level and the mechanism of their activation by ligands is unclear, still, TPCs are involved in severe human diseases such as viral translocation, bacterial infections, and cancers. To date, no approved drug targets them, increasing the urgent need to develop specific membrane-permeable molecules to block the NAADP-mediated calcium signaling via two-pore channels.
Recently published work in (Cell Calcium 75 (2018) 42-52) screened 1534 compounds for their ability to abolish NAADP mediated Ca2+release in sea urchin egg homogenates and cultured human cells. PF543, racecadotril, and SKF96365 were the top three ranked compounds that emerged from the screen. We propose synthesizing PF-543 analogs by introducing different chemical moieties in their structure to produce a specific TPC-blocker. We will use sea urchin egg homogenates to evaluate the potency of the TPC blocker and subsequent human cultured cells to validate the NAADP-evoked Ca2+release.
The known enzymatic inhibitory activity against sphingosine kinase and the abundance of information regarding the crystal structure of PF-543 at the enzyme active site are the reasons to choose PF-543 as a starting lead. PF-543 chemical structure contains three aromatic rings and hydroxymethyl pyrrolidine linked together using sulfoxide methylene linker and oxymethylene linker. We will explore the effects of different substituents in each ring and investigate the impact on NAADP- mediated calcium release to collect excellent structural activity relationship information for designing selective TPC antagonists.