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

Messick, Troy E.; Tolvinski, Lois; Zartler, Edward R.; Moberg, Anna; Frostell, Åsa; Smith, Garry R.; Reitz, Allen B.; Lieberman, Paul M.

doi:10.3390/molecules25071760

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

Journal Article · Fri Apr 10 00:00:00 EDT 2020 · Molecules

DOI:https://doi.org/10.3390/molecules25071760· OSTI ID:1630327

Messick, Troy E. ^[1]; Tolvinski, Lois ^[1]; Zartler, Edward R. ^[2]; Moberg, Anna ^[3]; Frostell, Åsa ^[3]; Smith, Garry R. ^[4]; Reitz, Allen B. ^[4]; Lieberman, Paul M. ^[1]

Wistar Inst., Philadelphia, PA (United States)
Quantum Tessera Consulting, LLC, Collegeville, PA (United States)
GE Healthcare Bio-Sciences AB, Uppsala (Sweden)
Fox Chase Chemical Diversity Center, Inc., Doylestown, PA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE; Wellcome Trust

OSTI ID:: 1630327

Journal Information:: Molecules, Journal Name: Molecules Journal Issue: 7 Vol. 25; ISSN 1420-3049

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
Epstein–Barr nuclear antigen 1
Epstein–Barr virus
Kaposi’s sarcoma associated herpesvirus (KSHV)
fragment-based lead discovery
latency-associated nuclear antigen
protein–DNA interaction
saturation transfer difference-nuclear magnetic resonance
surface plasmon resonance

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

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