Biophysical Screens Identify Fragments That Bind to the Viral DNA-Binding Proteins EBNA1 and LANA.

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.
Authors	Troy E Messick, Lois Tolvinski, Edward R Zartler, Anna Moberg, Åsa Frostell, Garry R Smith, Allen B Reitz, Paul M Lieberman
Journal	Molecules (Basel, Switzerland) (Molecules) Vol. 25 Issue 7 (Apr 10 2020) ISSN: 1420-3049 [Electronic] Switzerland
PMID	32290261 (Publication Type: Journal Article)
Chemical References	Antigens, Viral DNA, Viral DNA-Binding Proteins Epstein-Barr Virus Nuclear Antigens Ligands Nuclear Proteins Small Molecule Libraries latency-associated nuclear antigen EBV-encoded nuclear antigen 1
Topics	Antigens, Viral (chemistry, metabolism) DNA, Viral (chemistry, metabolism) DNA-Binding Proteins (chemistry, metabolism) Drug Discovery (methods) Epstein-Barr Virus Nuclear Antigens (chemistry, metabolism) Gammapapillomavirus Herpesvirus 4, Human Herpesvirus 8, Human (metabolism) Humans Ligands Magnetic Resonance Spectroscopy Models, Molecular Nuclear Proteins (chemistry, metabolism) Small Molecule Libraries Structure-Activity Relationship

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