Development of Murine Leukemia Virus Integrase-Derived Peptides That Bind Brd4 Extra-Terminal Domain as Candidates for Suppression of Acute Myeloid Leukemia.

ABSTRACT: The bromodomain and extra-terminal (BET) domain family of proteins, which include its prototypical member Brd4, is implicated in a variety of cancers and viral infections due to their interaction with cellular and viral proteins. BET proteins contain two bromodomains, a common protein motif that selectively binds acetylated lysine on histones. However, they are structurally distinct from other bromodomain-containing proteins because they encode a unique C-terminal extra-terminal (ET) domain that is important for the protein-protein interactions including jumonji C-domain-containing protein 6 (JMJD6) and histone-lysine N-methyltransferase NSD3 (NSD3). Brd4 functions primarily during transcription as a passive scaffold linking cellular and viral proteins to chromatin. The rapid development of clinical inhibitors targeting Brd4 highlights the importance of this protein as an anticancer target. Current therapeutic approaches focus on the development of small molecule acetylated lysine mimics of histone marks that block the ability of the bromodomains to bind their chromatin marks. Thus far, bromodomain-targeted agents have shown dose-limiting toxicities due to off-target effects on other bromodomain-containing proteins. Here, we exploited a viral-host protein interaction interface to design peptides for the disruption of BET protein function. A murine leukemia virus (MLV) integrase-derived peptide (ET binding motif, EBM) and its shorter minimal binding motif (pentapeptide LKIRL) were sufficient to directly bind the Brd4 ET domain and reduce cellular proliferation of an acute myeloid leukemia cell line. Using computational and biochemical approaches, we identified the minimal essential contacts between EBM and LKIRL peptides and the Brd4 ET domain. Our findings provide a structural foundation for inhibiting BET/Brd4-mediated cancers by targeting the ET domain with small peptide-based inhibitors.

SUBMITTER: Xing E 

PROVIDER: S-EPMC8506603 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature