Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase

Robert P. Hayes (), Mee Ra Heo, Mark Mason, John Reid, Christine Burlein, Kira A. Armacost, David M. Tellers, Izzat Raheem, Anthony W. Shaw, Edward Murray, Philip M. McKenna, Pravien Abeywickrema, Sujata Sharma, Stephen M. Soisson and Daniel Klein
Additional contact information
Robert P. Hayes: Computational and Structural Chemistry, Merck & Co., Inc.
Mee Ra Heo: Computational and Structural Chemistry, Merck & Co., Inc.
Mark Mason: Computational and Structural Chemistry, Merck & Co., Inc.
John Reid: Computational and Structural Chemistry, Merck & Co., Inc.
Christine Burlein: Quantitative Biosciences, Merck & Co., Inc.
Kira A. Armacost: Computational and Structural Chemistry, Merck & Co., Inc.
David M. Tellers: Discovery Chemistry, Merck & Co., Inc.
Izzat Raheem: Discovery Chemistry, Merck & Co., Inc.
Anthony W. Shaw: Discovery Chemistry, Merck & Co., Inc.
Edward Murray: Infectious Diseases and Vaccines, Merck & Co., Inc.
Philip M. McKenna: Infectious Diseases and Vaccines, Merck & Co., Inc.
Pravien Abeywickrema: Computational and Structural Chemistry, Merck & Co., Inc.
Sujata Sharma: Computational and Structural Chemistry, Merck & Co., Inc.
Stephen M. Soisson: Computational and Structural Chemistry, Merck & Co., Inc.
Daniel Klein: Computational and Structural Chemistry, Merck & Co., Inc.

Nature Communications, 2021, vol. 12, issue 1, 1-7

Abstract: Abstract All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU bound at the polymerase active site, displacing the template strand and inducing a conformational shift of the fingers domain into an open state. These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing inhibitor (NCI). Sequence conservation of the NCI binding pocket further explains broad-spectrum activity while a direct interaction between PNU and residue V823 rationalizes why mutations at this position result in loss of inhibition.

Date: 2021
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DOI: 10.1038/s41467-021-23312-8

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