Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol-dependent cytolysins.

ABSTRACT: Certain species of pathogenic bacteria damage tissues by secreting cholesterol-dependent cytolysins, which form pores in the plasma membranes of animal cells. However, reducing cholesterol protects cells against these cytolysins. As the first committed step of cholesterol biosynthesis is catalyzed by squalene synthase, we explored whether inhibiting this enzyme protected cells against cholesterol-dependent cytolysins. We first synthesized 22 different nitrogen-containing bisphosphonate molecules that were designed to inhibit squalene synthase. Squalene synthase inhibition was quantified using a cell-free enzyme assay, and validated by computer modeling of bisphosphonate molecules binding to squalene synthase. The bisphosphonates were then screened for their ability to protect HeLa cells ag

SUBMITTER: Pospiech M 

PROVIDER: S-EPMC12315948 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature