8VQ2

HSV1 polymerase ternary complex with dsDNA and compound 44

This is a non-PDB format compatible entry.

Summary for 8VQ2

• Entry DOI: 10.2210/pdb8vq2/pdb
• Descriptor: DNA polymerase, DNA (5'-D(P*TP*GP*GP*TP*AP*GP*GP*GP*GP*AP*AP*GP*GP*AP*T)-3'), DNA (5'-D(P*AP*TP*CP*CP*TP*TP*CP*CP*CP*CP*TP*AP*C)-3'), ... (4 entities in total)
• Functional Keywords: herpesvirus polymerase complex inhibitor, transferase
• Biological source: Human alphaherpesvirus 1 (Herpes simplex virus type 1); More
• Total number of polymer chains: 6
• Total formula weight: 277265.65

Authors

Hayes, R.P.,Heo, M.R.,Plotkin, M. (deposition date: 2024-01-17, release date: 2024-08-28)

Primary citation

Plotkin, M.A.,Labroli, M.,Schubert, J.,Shaw, A.,Schlegel, K.S.,Berger, R.,Cooke, A.J.,Hayes, R.P.,Armacost, K.A.,Kinek, K.,Krosky, P.,Burlein, C.,Meng, S.,DiNunzio, E.,Murray, E.M.,Agrawal, S.,Madeira, M.,Flattery, A.,Yao, H.,Leithead, A.,Rose 2nd, W.A.,Cox, C.,Tellers, D.M.,McKenna, P.M.,Raheem, I.
Discovery of Broad-Spectrum Herpes Antiviral Oxazolidinone Amide Derivatives and Their Structure-Activity Relationships.
Acs Med.Chem.Lett., 15:1232-1241, 2024

PubMed Abstract: Herpesvirus 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 () with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV infection.

PubMed: 39140041
DOI: 10.1021/acsmedchemlett.4c00117

Experimental method

X-RAY DIFFRACTION (3.829 Å)