8vq2
HSV1 polymerase ternary complex with dsDNA and compound 44
Structural highlights
FunctionI7GY94_HHV1 Replicates viral genomic DNA. The replication complex is composed of six viral proteins: the DNA polymerase, processivity factor, primase, primase-associated factor, helicase, and ssDNA-binding protein. Additionally, the polymerase contains an intrinsic ribonuclease H (RNase H) activity that specifically degrades RNA/DNA heteroduplexes or duplex DNA substrates in the 5' to 3' direction. Therefore, it can catalyze the excision of the RNA primers that initiate the synthesis of Okazaki fragments at a replication fork during viral DNA replication.[ARBA:ARBA00025601] Publication Abstract from PubMedHerpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity. Herpesviruses share a conserved DNA polymerase, the inhibition of which is validated as an effective strategy to disrupt viral replication. By utilizing a non-nucleoside inhibitor of the viral DNA polymerase, we sought to develop agents covering multiple herpesviruses (e.g., CMV, VZV, HSV1/2, EBV, and HHV6). Herein is described the invention of an oxazolidinone class of broad-spectrum non-nucleoside herpes antiviral inhibitors. A lead compound (42) with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV infection. Discovery of Broad-Spectrum Herpes Antiviral Oxazolidinone Amide Derivatives and Their Structure-Activity Relationships.,Plotkin MA, Labroli M, Schubert J, Shaw A, Schlegel KS, Berger R, Cooke AJ, Hayes RP, Armacost KA, Kinek K, Krosky P, Burlein C, Meng S, DiNunzio E, Murray EM, Agrawal S, Madeira M, Flattery A, Yao H, Leithead A, Rose WA 2nd, Cox C, Tellers DM, McKenna PM, Raheem I ACS Med Chem Lett. 2024 Jul 9;15(8):1232-1241. doi: , 10.1021/acsmedchemlett.4c00117. eCollection 2024 Aug 8. PMID:39140041[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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