Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents | Sciact - CRIS-system of Boreskov Institute of Catalysis

Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents Full article

Journal

Molecules
ISSN: 1420-3049

Output data

Year: 2023, Volume: 28, Number: 21, Article number : 7375, Pages count : 22 DOI: 10.3390/molecules28217375

Tags

herpes simplex virus; in vitro antiviral activity; drug resistance; high-throughput sequencing; mutation analysis; molecular docking; molecular dynamic simulations

Authors

Krasnov Victor P. ¹ , Andronova Valeriya L. ² , Belyavsky Alexander V. ³ , Borisevich Sophia S. ⁴ , Galegov George A. ² , Kandarakov Oleg F. ³ , Gruzdev Dmitry A. ¹ , Vozdvizhenskaya Olga A. ¹ , Levit Galina L. ¹

Affiliations

1	Postovsky Institute of Organic Synthesis, Russian Academy of Sciences (Ural Branch), Ekaterinburg 620108, Russia
2	Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia
3	Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
4	Ufa Institute of Chemistry, Russian Academy of Sciences, Ufa 450078, Russia

Herpes simplex virus type 1 (HSV-1) is an extremely widespread pathogen characterized by recurrent infections. HSV-1 most commonly causes painful blisters or sores around the mouth or on the genitals, but it can also cause keratitis or, rarely, encephalitis. First-line and second-line antiviral drugs used to treat HSV infections, acyclovir and related compounds, as well as foscarnet and cidofovir, selectively inhibit herpesvirus DNA polymerase (DNA-pol). It has been previously found that (S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (compound 1) exhibits selective anti-herpesvirus activity against HSV-1 in cell culture, including acyclovir-resistant mutants, so we consider it as a lead compound. In this work, the selection of HSV-1 clones resistant to the lead compound was carried out. High-throughput sequencing of resistant clones and reference HSV-1/L2 parent strain was performed to identify the genetic determinants of the virus’s resistance to the lead compound. We identified a candidate mutation presumably associated with resistance to the virus, namely the T321I mutation in the UL15 gene encoding the large terminase subunit. Molecular modeling was used to evaluate the affinity and dynamics of the lead compound binding to the putative terminase binding site. The results obtained suggest that the lead compound, by binding to pUL15, affects the terminase complex. pUL15, which is directly involved in the processing and packaging of viral DNA, is one of the crucial components of the HSV terminase complex. The loss of its functional activity leads to disruption of the formation of mature virions, so it represents a promising drug target. The discovery of anti-herpesvirus agents that affect biotargets other than DNA polymerase will expand our possibilities of targeting HSV infections, including those resistant to baseline drugs.

Krasnov V.P. , Andronova V.L. , Belyavsky A.V. , Borisevich S.S. , Galegov G.A. , Kandarakov O.F. , Gruzdev D.A. , Vozdvizhenskaya O.A. , Levit G.L.
Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents
Molecules. 2023. V.28. N21. 7375 :1-22. DOI: 10.3390/molecules28217375 WOS Scopus ANCAN PMID OpenAlex

Submitted:	Sep 13, 2023
Accepted:	Oct 23, 2023
Published online:	Oct 31, 2023
Published print:	Nov 1, 2023

Web of science:	WOS:001099589500001
Scopus:	2-s2.0-85176581207
Chemical Abstracts:	2023:2385049
Chemical Abstracts (print):	185:78019
PMID:	37959793
OpenAlex:	W4388084962

DB	Citing
OpenAlex	3
Web of science	1
Scopus	2