Inhibition of Cystathionine Beta-Synthase Greatly Reduces Cell Death Following Stroke

Here I'll point out recently published results for a cystathionine beta-synthase inhibitor drug candidate. The researchers involved have demonstrated that in rats it greatly reduces cell death in brain tissue following stroke:

Most strokes occur when a disruption of blood flow prevents oxygen and glucose from reaching brain tissue, ultimately killing neurons and other cells. The team found that its molecule, known as 6S, reduced the death of brain tissue by as much as 66 percent when administered to the cerebrum of a rat that had recently suffered a stroke. It also appeared to reduce the inflammation that typically accompanies stroke. "The fact that this inhibitor remained effective when given as post-stroke treatment is encouraging, as this is the norm in the treatment of acute stroke."

The inhibitor works by binding to cystathionine beta-synthase, or CBS - an enzyme that normally helps regulate cellular function but can also trigger production of toxic levels of hydrogen sulfide in the brain. Though hydrogen sulfide is an important signaling molecule at normal concentrations, stroke patients exhibit elevated concentrations believed to initiate the brain damage they often suffer. Researchers modeled their inhibitor on a naturally occurring molecule produced by the CBS enzyme, tailoring the molecule's structure to improve its performance. By swapping out functional groups of atoms known as amines with hydrazines, the team ultimately increased the inhibitor's binding time from less than a second to hours. "We wanted a compound that would bind well, specifically to this enzyme. But we also wanted one that could be synthesized easily. Those are two very different considerations." The team achieved the latter goal, in part, by plucking out the molecule's carbon-sulfur bond and replacing it with a double bond. Slicing that double bond gave the researchers two identical halves of the molecule.

Because the 6S inhibitor has demonstrated its effects in cell cultures and the brain tissue of rats, it represents just an initial step toward developing a stroke-treating drug for humans. However, the proof-of-principle experiments effectively illustrate the concept's promise. The researchers expressed optimism that the synthesis method detailed in the study could streamline the more general production of enzyme-targeting inhibitors. "We started out with a very fundamental-science perspective on understanding the chemistry of this whole class of vitamin B6-dependent enzymes. We're in a good place now, because that science has allowed us to make these inhibitors and many others. We're now working on several enzymes that may represent important targets for translation of the basic inhibitor chemistry into truly therapeutic goals."



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