Valproic acid

Valproic acid (VPA), formally 2-propylpentanoic acid, is a low–molecular weight branched-chain fatty acid. It is a derivative of valeric (pentanoic) acid1, which occurs naturally in valerian (Valeriana officinalis), an Eastern Hemisphere flowering plant.

VPA has been known since at least the 1880s, when it was synthesized by American chemist Beverly S. Burton. In 1915, a monumental work on optically active fatty acids by Emil Abderhagen and Egon Eichwald at the University of Halle (Germany) reported that VPA was optically active, even though an inspection of its structure shows that that cannot be true.

VPA is widely used for treating several diseases, including epilepsy and bipolar disorder. Until the 1960s, it was used only as a solvent for pharmaceuticals and some industrial chemicals; but in 1963, George Carraz and colleagues at Laboratoire Berthier (Grenoble, France) discovered that all of the compounds they were testing for anticonvulsant activity gave positive results when they were dissolved in VPA. This serendipitous finding led to France’s approval of VPA for treating epilepsy in 1967. The US Food and Drug Administration granted similar approval in 1978.

VPA is well known for inhibiting histone deacetylases, enzymes that allow histone proteins to wrap DNA more tightly than they otherwise would. It also has the ability to reduce the stability of certain proteins, including Cas9 (CRISPR-associated protein 9), which plays an important role in prokaryotic adaptive immunity. Its precise mechanism-of-action for destabilizing Cas9, however, is still largely unknown.