Abstract
The human gamma-herpesviruses Epstein–Barr virus (EBV) (HHV-4) and Kaposi’s sarcoma-associated herpesvirus (KSHV) (HHV-8) are responsible for a number of diseases, including various types of cancer. Epstein–Barr nuclear antigen 1 (EBNA1) from EBV and latency-associated nuclear antigen (LANA) from KSHV are viral-encoded DNA-binding proteins that are essential for the replication and maintenance of their respective viral genomes during latent, oncogenic infection. As such, EBNA1 and LANA are attractive targets for the development of small-molecule inhibitors. To this end, we performed a biophysical screen of EBNA1 and LANA using a fragment library by saturation transfer difference (STD)–NMR spectroscopy and surface plasmon resonance (SPR). We identified and validated a number of unique fragment hits that bind to EBNA1 or LANA. We also determined the high-resolution crystal structure of one fragment bound to EBNA1. Results from this screening cascade provide new chemical starting points for the further development of potent inhibitors for this class of viral proteins.
Highlights
Small-molecule disruption of macromolecular interactions is becoming an increasingly important strategy for developing new therapies to treat human diseases
To provide additional chemical starting points using a more unbiased initial screen for Epstein–Barr nuclear antigen 1 (EBNA1) and to identify initial fragment hits for latency-associated nuclear antigen (LANA), we report here the screening of a 1000 fragment library by saturation transfer difference (STD)–NMR and surface plasmon resonance (SPR)
The fragment library was selected based on in silico docking to a site to a site thought be important for DNA
Summary
Small-molecule disruption of macromolecular interactions is becoming an increasingly important strategy for developing new therapies to treat human diseases Discovery of these inhibitors can be challenging due to the diversity of interactions that must be satisfied by a small molecule to compete with the interactions between macromolecules [1]. Another challenge is the relatively limited collection of existing high-throughput libraries compared with theoretical chemical space. Despite these challenges, there have been a number of successes—including clinically—of inhibitors of protein–protein interactions (PPIs) [2,3,4]. Efforts to discover small-molecule inhibitors that target these protein–DNA interactions remain in a relatively early stage [5]
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