An international research team led by the St. Jude Children’s Research Hospital and the UT Southwestern Medical Center has clarified how certain antiepileptic drugs bind to their target protein. The focus is on synaptic vesicle glycoprotein 2A (SV2A), a membrane protein found in almost all neurons and targeted by drugs such as levetiracetam. Levetiracetam is also the only 3D-printed drug approved to date by the U.S. Food and Drug Administration – reason enough to examine its molecular mechanism of action in more detail.
With the help of cryo-electron microscopy, the researchers determined the structure of SV2A both in its unbound state and in complexes with approved and experimental active substances.
“There are several compounds that bind to SV2A, but its biology is still largely unknown; its native substrate hasn’t even been identified,” explained co-corresponding author Chia-Hsueh Lee, PhD, St. Jude Department of Structural Biology. “SV2A is highly expressed in neurons, so its medical importance and unknown biology motivated us to learn more.”
The high-resolution structures show how levetiracetam and brivaracetam use a primary binding pocket and trigger typical conformational changes of this transporter family.
In addition, the team characterized a second, allosteric binding site. Modulators bind there that can enhance the effect of the primary ligands. The comparison with the developmental drug padsevonil is particularly interesting: it addresses both binding sites at the same time and behaves structurally differently from levetiracetam and brivaracetam. From Lee’s perspective, this offers a starting point for more selective compounds: the allosteric center is less conserved between different transporters than the primary pocket, making it possible to target SV2A specifically.
“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,” Lee said. “This will allow therapies to be more specific to SV2A, rather than drugs that inhibit other superfamily members and cause side effects.”
“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.”
For the 3D printing community, the work is an example of how additive manufacturing and drug design need to be considered together. Precise structural data open up possibilities for combinations of custom tablet shapes, variable dosages and optimized binding properties. Lee and his team plan to further clarify the role of SV2A in neurons – also to develop better modulators that can be used to specifically target the protein in future drugs.
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