A team of researchers from St. Jude Children's Research Hospital and UT Southwestern Medical Center has, for the first time, mapped how certain anti-epilepsy drugs interact with their target protein in the brain. The study, published in Nature Communications, used cryo-electron microscopy to observe structural changes in synaptic vesicle glycoprotein 2A (SV2A), a protein found in almost all neurons.
The researchers examined how FDA-approved drugs such as levetiracetam and brivaracetam, as well as experimental therapies, bind to SV2A. They also explored how some modulators can attach to an alternative site on the protein—known as an allosteric site—to enhance drug potency.
Chia-Hsueh Lee, PhD, co-corresponding author from St. Jude's Department of Structural Biology, said: "There are several compounds that bind to SV2A, but its biology is still largely unknown; its native substrate hasn't even been identified. SV2A is highly expressed in neurons, so its medical importance and unknown biology motivated us to learn more."
Levetiracetam is notable as the only three-dimensional printed drug product approved by the Food & Drug Administration and is included on the World Health Organization's Essential Medicines List.
The research team determined structures of SV2A alone and bound with various anti-seizure drugs. Their findings showed that while levetiracetam and brivaracetam bind only at the primary site of SV2A—causing typical structural changes—padsevonil binds both the primary and allosteric sites. This distinction could explain differences in drug efficacy and side effects.
Lee explained: "Across the different members of this transporter family, the primary drug site is more conserved than the allosteric site. So, if you want a more specific compound, you should design it to bind only to the allosteric site. This will allow therapies to be more specific to SV2A, rather than drugs that inhibit other superfamily members and cause side effects."
Lee continues research into SV2A’s biological role in neurons. "Developing better inhibitors or modulators will allow us to dissect SV2A's functions and determine whether it truly works as a transporter," Lee said. "The more we understand this protein, even from a pharmacological perspective, the more tools we have to control or modulate it."
The study’s first author is Shabareesh Pidathala from St. Jude. Other contributors include Fangyu Liu (co-corresponding author) from UT Southwestern Medical Center; Long Nguyen from National University of Singapore; Yiming Niu from The Rockefeller University; and Xiao Chen, Yaxin Dai, and Christoph Gorgulla from St. Jude.
Funding for this research came from the National Institutes of Health (R01NS133147) and American Lebanese Syrian Associated Charities (ALSAC), which supports fundraising efforts for St. Jude.
