O4‐01‐01: Inhibiting Amyloid‐beta Cytotoxicity Through Its Interaction With the Cell Surface Receptor Lilrb2 by Structure‐based Design
Year: 2019
Type: article
Abstract: Inhibiting the interaction between ß-amyloid (Aß) and a neuronal cell surface receptor, LilrB2, have been suggested as potential route for treating Alzheimer's disease (AD). Supporting this approach, AD-like symptoms are reduced in mouse models following genetic depletion of the LilrB2 homolog. In its pathogenic, oligomeric state, Aß binds to LilrB2, triggering a pathway to synaptic loss. To identify suitable therapeutic targets for designing new drugs to inhibit Aß toxicity for Alzheimer's diseases, we integrated structural, computational, and cellular approaches to elucidate the underlying mechanisms. Here we identified the LilrB2 binding moieties of Aß (KLVFFA) and identified its binding site on LilrB2 from a crystal structure of LilrB2 immunoglobulin domains D1D2 complexed to small molecules that mimic phenylalanine residues. In this structure, we observed two pockets that can accommodate the phenylalanine sidechains of KLVFFA. These pockets were confirmed to be KLVFFA binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Aß-LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Aß-LilrB2 interactions in vitro and on the cell surface and reduce Aß cytotoxicity, which suggests these inhibitors are potential therapeutic leads against AD. The identified binding sites of Aβ and LilrB2 led to brain-penetrating inhibitors that block Aβ-LilrB2 interaction and rescue Aβ-induced cytotoxicity, which highlights the therapeutic values of these drug candidates for treating Alzheimer's disease.
Source: Alzheimer s & Dementia
Institution: University of California, Los Angeles
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2981288980